Agonists of bitter taste receptors and uses thereof

ABSTRACT

The present invention relates to agonists of the human bitter-taste receptors hTAS2R14, hTAS2R10 and hTAS2R4 and their role in bitter taste transduction. The invention also relates to methods for identifying molecules that modulate, e.g. suppress, or enhance hTAS2R14, hTAS2R10 and hTAS2R4 bitter taste transduction or bitter taste response.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.12/593,479, filed Sep. 28, 2009, which is a §371 National StageApplication of PCT/EP2008/002529, filed Mar. 31, 2008, which claimspriority to European Application 07006595.8, filed Mar. 29, 2007, andU.S. Application No. 60/921,157, filed Mar. 29, 2007, the contents ofeach are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to agonists of the human bitter-tastereceptors hTAS2R14, hTAS2R10 and hTAS2R4 and their role in bitter tastetransduction. The invention also relates to methods for identifyingmolecules that modulate, e.g. suppress, or enhance hTAS2R14, hTAS2R10and hTAS2R4 bitter taste transduction or bitter taste response.

BACKGROUND OF THE INVENTION

Investigators have recently turned their attention to understanding thebiological mechanisms of taste, and in particular bitter taste. For areview of the literature see, for example, Caicedo A. and Roper S D.(2001) Science 291: 1557-1560; Dulac C. (2000) Cell 100: 607-610;Kinnamon S. C. (2000) Neuron 25: 507-510; Lindemann B. (2001) Nature413: 219-225.; and Margolskee R F. (2001) J. Biol. Chem. 277: 1-4.

Bitter taste is aversive, and as such provides humans with a mechanismof protection against poisonous substances, which are generallybitter-tasting compounds. More subtly, bitter-tastants also affect thepalatability of food, beverages, thereby influencing human nutritionalhabits as is more fully discussed by Drewnowski in “The Science andComplexity of Bitter Taste”, (2001) Nutr. Rev. 59: 163-169. They alsoaffect the palatability of other ingestibles such as orally administeredpharmaceuticals and nutraceuticals. Understanding the mechanism ofbitter taste transduction has implications for the food andpharmaceutical industries. If the bitter taste transduction pathway canbe manipulated, it may be possible to suppress or eliminate bitter tasteto render foods more palatable and increase patient compliance with oralpharmaceutics.

Taste transduction involves the interaction of molecules, i.e. tastantswith taste receptor-expressing cells which reside in the taste budslocated in the papillae of the tongue. Taste buds relay information tothe brain on the nutrient content of food and the presence of poisons.Recent advances in biochemical and physiological studies have enabledresearchers to conclude that bitter taste transduction is mediated byso-called G-protein coupled receptors (GPCRs). GPCRs are 7 transmembranedomain cell surface proteins that amplify signals generated at a cellsurface when the receptor interacts with a ligand (a tastant) whereuponthey activate heterotrimeric G-proteins. The G-proteins are proteincomplexes that are composed of alpha and beta-gamma sub-units. They areusually referred to by their alpha subunits and classified generallyinto 4 groups: G alpha s, i, q and 12. The G alpha q type couple withGPCRs to activate phospholipase C which leads to an increase in cellularCa²⁺. There are many Gq-type G-proteins that are promiscuous and cancouple to GPCRs, including taste receptors, and these so-called“promiscuous” G-proteins are well known in the art. These G-proteinsdissociate into alpha and beta-gamma subunits upon activation, resultingin a complex cascade of cellular events that results in the cellproducing second messengers, such as calcium ions, that enable the cellsto send a signal to the brain indicating a bitter response.

There is also anatomical evidence that GPCRs mediate bitter tastetransduction: clusters of these receptors are found in mammalian tastecells containing gustducin. Gustducin is a G-protein subunit that isimplicated in the perception of bitter taste in mammals see, forexample, Chandrashekar, J. et al (2000) Cell 100: 703-711; Matsunami H.et al. (2000) Nature 404: 601-604; or Adler E. et al. (2000) Cell 100:693-702. cDNAs encoding such GPCRs have been identified, isolated, andused as templates to compare with DNA libraries using in-silicodata-mining techniques to identify other related receptors. In thismanner it has been possible to identify a family of related receptors,the so-called T2R or TAS2R family of receptors, that have beenputatively assigned as bitter taste receptors.

Humans are able to detect with a limited genetic repertoire of about 30receptor genes thousands of different bitter compounds. Since theirdiscovery in the year 2000 (Adler E. et al. (2000) supra; ChandrashekarJ. et al. (2000) supra; Matsunami H. et al (2000) supra) only fewmammalian TAS2Rs have been deorphanised, i.e. ligands, in particularagonists have been identified. The murine mTAS2R5 (Chandrashekar J. etal (2000) supra) and the rat rTAS2R9 (Bufe B. et al. (2002) NatureGenetics 32:397-401) respond to the toxic bitter substancecycloheximide, the mouse mTAS2R8 and the human hTAS2R4 respond to highdoses of denatonium and, to a lesser extend, to 6-n-propyl-2-thiouracil(Chandrashekar J. et al. (2000) supra), the human hTAS2R10 and hTAS2R16respond selectively to strychnine and bitterglucopyranosides,respectively (Bufe B. et al (2002) supra). Although for some TAS2Rs alimited promiscuity (mTAS2R8, hTAS2R4) or specificity for a group ofchemically related compounds (hTAS2R16) was reported, the relativeselectivity of ligand recognition by the receptors published to datedoes, by far, not explain the enormous number of bitter tastantsrecognised by the mammalian gustatory system. There are several possiblemechanisms conceivable to increase the number of tastants recognised bya limited number of taste receptor genes, the simplest way would be tohave receptors which exhibit a broad tuning to a great number ofstructurally divergent ligands.

As stated before, thousands of different bitter compounds can elicitbitter taste. Consequently, not all bitter tasting substances can beprevented to elicit bitter taste by blocking only a small subset ofreceptors within the bitter taste receptor family. In order to carry outa method for isolating additional agonists or antagonists to complementalready known ones, it is therefore necessary to deorphanize bittertaste receptors and gain insight in what particular agonists aretargeting the receptors for which no agonists or antagonists are known.The knowledge about the receptor specificity for a given agonist isprerequisite to the implementation of a method to isolate structurallyrelated agonists or antagonists which may be at least as potent inactivating or suppressing the bitter taste receptor activity as theoriginal compound and which may feature additional advantages such aslower toxicity, better solubility, improved stability and so forth. Abitter taste receptor agonist isolated by such method can furthermore beutilized to identify a respective antagonist for the same receptor.Furthermore, agonists and antagonists can be isolated and modified insuch a way that they are capable of targeting a broader range of knownbitter taste receptors with high affinity to achieve a more effectiveenhancement or suppression of bitter taste.

In addition to the deorphanization of the human bitter taste receptorhTAS2R4, the present inventors teach that the human bitter tastereceptors hTAS2R14, hTAS2R10 and hTAS2R4, respond to specific bittercompounds, namely, to a bitter compound selected from the groupconsisting of absinthin, artemorin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, chlorhexidine, N,N′-diethylthiourea, herbolidA, isohumulone, noscapine, parthenolid, or arborescin for hTAS2R14; to abitter compound selected from the group consisting of absinthin,artemorin, amarogentin, arglabin, azathioprine, benzoin, camphor,cascarillin, papaverin, parthenolid, picrotoxinin, arborescin or(−)-a-thujon for hTAS2R10; or to a bitter compound selected from thegroup consisting of artemorin, amarogentin, azathioprine or campor forhTAS2R4. Therefore, the disclosure of the present patent applicationallows the implementation of a method to isolate effective agonists orantagonists for particularly these receptors.

DESCRIPTION OF THE INVENTION

Before the present invention is described in detail below, it is to beunderstood that this invention is not limited to the particularmethodology, protocols and reagents described herein as these may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the present invention which will be limited onlyby the appended claims. Unless defined otherwise, all technical andscientific terms used herein have the same meanings as commonlyunderstood by one of ordinary skill in the art.

Preferably, the terms used herein are defined as described in “Amultilingual glossary of biotechnological terms: (IUPACRecommendations)”, Leuenberger, H. G. W, Nagel, B. and Klbl, H. eds.(1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps. Inthe following passages different aspects of the invention are defined inmore detail. Each aspect so defined may be combined with any otheraspect or aspects unless clearly indicated to the contrary. Inparticular, any feature indicated as being preferred or advantageous maybe combined with any other feature or features indicated as beingpreferred or advantageous.

Several documents are cited throughout the text of this specification.Each of the documents cited herein (including all patents, patentapplications, scientific publications, manufacturer's specifications,instructions, etc.), whether supra or infra, are hereby incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

In the following definitions of the terms: alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, alicyclic system, aryl, aralkyl,heteroaryl, heteroaralkyl, alkenyl and alkynyl are provided. These termswill in each instance of its use in the remainder of the specificationhave the respectively defined meaning and preferred meanings.

The term “alkyl” refers to a saturated straight or branched carbonchain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e.1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl,propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl,or octyl. Alkyl groups are optionally substituted.

The term “heteroalkyl” refers to a saturated straight or branched carbonchain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e. 1,2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, which isinterrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same ordifferent heteroatoms. Preferably the heteroatoms are selected from O,S, and N, e.g. —O—CH₃, —S—CH₃, —CH₂—O—CH₃, —CH₂—O—C₂H₅, —CH₂—S—CH₃,—CH₂—S—C₂H₅, —C₂H₄—O—CH₃, —C₂H₄—O—C₂H₅, —C₂H₄—S—CH₃, —C₂H₄—S—C₂H₅ etc.Heteroalkyl groups are optionally substituted.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively, with preferably 3,4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. Theterms “cycloalkyl” and “heterocycloalkyl” are also meant to includebicyclic, tricyclic and polycyclic versions thereof. If more than onecyclic ring is present such as in bicyclic, tricyclic and polycyclicversions, then these rings may also comprise one or more aryl- orheteroaryl ring. The term “heterocycloalkyl” preferably refers to asaturated ring having five members of which at least one member is a N,O or S atom and which optionally contains one additional O or oneadditional N; a saturated ring having six members of which at least onemember is a N, O or S atom and which optionally contains one additionalO or one additional N or two additional N atoms; or a saturated bicyclicring having nine or ten members of which at least one member is a N, Oor S atom and which optionally contains one, two or three additional Natoms.

“Cycloalkyl” and “heterocycloalkyl” groups are optionally substituted.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Preferred examples of cycloalkyl include C₃-C₁₀-cycloalkyl, inparticular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly,or decahydro-naphthalenyl. Preferred examples of heterocycloalkylinclude C₃-C₁₀-heterocycloalkyl, in particular1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5]decyl,1,7 diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The term “alicyclic system” refers to mono, bicyclic, tricyclic orpolycyclic version of a cycloalkyl or heterocycloalkyl comprising atleast one double and/or triple bond. However, an alicyclic system is notaromatic or heteroaromatic, i.e. does not have a system of conjugateddouble bonds/free electron pairs. Thus, the number of double and/ortriple bonds maximally allowed in an alicyclic system is determined bythe number of ring atoms, e.g. in a ring system with up to 5 ring atomsan alicyclic system comprises up to one double bond, in a ring systemwith 6 ring atoms the alicyclic system comprises up to two double bonds.Thus, the “cycloalkenyl” as defined below is a preferred embodiment ofan alicyclic ring system. Alicyclic systems are optionally substituted.Alicyclic systems comprise one, two, three or more heteroatoms,independently selected from the group consisting of nitrogen, sulphurand oxygen.

The term “aryl” preferably refers to an aromatic monocyclic ringcontaining 6 carbon atoms, an aromatic bicyclic ring system containing10 carbon atoms or an aromatic tricyclic ring system containing 14carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The arylgroup is optionally substituted.

The term “aralkyl” refers to an alkyl moiety, which is substituted byaryl, wherein alkyl and aryl have the meaning as outlined above. Anexample is the benzyl radical. Preferably, in this context the alkylchain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or8, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, sec-butenyl, tert-butyl, pentyl, hexyl, pentyl, octyl. Thearalkyl group is optionally substituted at the alkyl and/or aryl part ofthe group.

The term “heteroaryl” preferably refers to a five or six-memberedaromatic monocyclic ring wherein at least one of the carbon atoms arereplaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or5 (for the six membered ring) of the same or different heteroatoms,preferably selected from O, N and S; an aromatic bicyclic ring systemwherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12carbon atoms have been replaced with the same or different heteroatoms,preferably selected from O, N and S; or an aromatic tricyclic ringsystem wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16carbon atoms have been replaced with the same or different heteroatoms,preferably selected from O, N and S. Examples are oxazolyl, isoxazolyl,1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl,1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl,1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl,indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl,benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl.

The term “heteroaralkyl” refers to an alkyl moiety, which is substitutedby heteroaryl, wherein alkyl and heteroaryl have the meaning as outlinedabove. An example is the 2-alklypyridinyl, 3-alkylpyridinyl, or2-methylpyridinyl. Preferably, in this context the alkyl chain comprisesfrom 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl,ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butenyl,tert-butyl, pentyl, hexyl, pentyl, octyl. The heteroaralkyl group isoptionally substituted at the alkyl and/or heteroaryl part of the group.

The terms “alkenyl” and “cycloalkenyl” refer to olefinic unsaturatedcarbon atoms containing chains or rings with one or more double bonds.Examples are propenyl and cyclohexenyl. Preferably, the alkenyl chaincomprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl,3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, hexenyl, heptenyl, octenyl. The term also comprises CH₂,i.e. methenyl, if the substituent is directly bonded via a double bondto the carbon atom to which it is attached. Preferably the cycloalkenylring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl,spiro[3,3]heptenyl, spiro[3,4]octenyl, spiro[4,3]octenyl,spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl,spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl,bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl,bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl,hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, oroctahydro-naphthalenyl.

The term “alkynyl” refers to unsaturated carbon atoms containing chainsor rings with one or more triple bonds. An example is the propargylradical. Preferably, the alkynyl chain comprises from 2 to 8 carbonatoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.

The term “optionally substituted” in each instance if not furtherspecified preferably refers to halogen, preferably, F, Cl, or Br, —NO₂,—CN, —OR′, —NR′R″, —COOR′, —CONR′R″, —NR′″COR′″, —NR′″COR′″, ═O, ═S,—NR′″CONR′R″, —NR″SO₂A, —COR′″, —SO₂NR′R″, —OOCR′″, —CR′″R′″OH, R′″OH,and -E or two substituents at adjacent carbon moieties orheteromoieties, as the case may be, form a cycloalkyl, heterocycloalkly,alicyclic system, aryl or heteroaryl;

R′ and R″ is each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, and aralkyl or together form a heteroaryl, orheterocycloalkyl;

R′″ and R″″ is each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy,aryl, aralkyl, heteroaryl, and —NR′R″;

E is selected from the group consisting of alkyl, alkenyl, cycloalkyl,alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl andheteroaryl; optionally substituted;

The present inventors have identified an agonist of the human hTAS2R14(DNA sequence according to SEQ ID NO: 1 and amino acid sequenceaccording to SEQ ID NO: 2), hTAS2R10 (DNA sequence according to SEQ IDNO: 3 and amino acid sequence according to SEQ ID NO: 4) and hTAS2R4(DNA sequence according to SEQ ID NO: 5 and amino acid sequenceaccording to SEQ ID NO: 6) bitter taste receptors, and have found thatthey respond with specificity toward the following bitter substances:absinthin, artemorin, arglabin, azathioprine, azepinon, benzoin,brucine, camphor, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, parthenolid, or arborescin for hTAS2R14;absinthin, artemorin, amarogentin, arglabin, azathioprine, benzoin,camphor, cascarillin, papaverin, parthenolid, picrotoxinin, arborescinand (−)-a-thujon for hTAS2R10; and artemorin, amarogentin, azathioprineor campor for hTAS2R4—an important finding for the food andpharmaceutical industries. The agonist provided by the present inventorsenables the skilled person to design intelligent compound libraries toscreen for antagonists to the bitter response of these receptors, whichin turn enables the development of compounds and compositions tosuppress or eliminate bitter tasting components of foods, in particularanimal foods, nutrients and dietary supplements and pharmaceutical orhomeopathic preparations containing such phytochemicals. Similarly, theinvention also enables the skilled person to screen for additionalstructurally related agonists, or to screen for compounds that enhance abitter response, such as might be useful in the food industry and in theproduction of animal repellents. Therefore, in one aspect the presentinvention provides a method for isolating an antagonist of hTAS2R14,hTAS2R10 or hTAS2R4 bitter taste receptor activity, wherein the bittertaste receptor is encoded by a polynucleotide selected from the groupconsisting of:

-   (a) polynucleotide encoding at least the mature form of the    polypeptide having the amino acid sequence as shown in SEQ ID NO: 2,    4, or 6;-   (b) polynucleotide having the coding nucleotide sequence as shown in    SEQ ID NO: 1, 3, or 5 encoding at least the mature form of the    polypeptide;-   (c) polynucleotide encoding a fragment or derivative of a    polypeptide encoded by a polynucleotide of any one of (a) to (b),    wherein in said derivative one or more amino acid residues are    conservatively substituted compared to said polypeptide, and said    fragment or derivative has hTAS2R14, hTAS2R10 and hTAS2R4 bitter    taste receptor activity, respectively;-   (d) polynucleotide which is an ortholog of the polynucleotide    sequences shown in SEQ ID NO: 1, 3, or 5 encoding at least the    mature form of the corresponding bitter taste receptor;-   (e) polynucleotide which encodes a polypeptide having hTAS2R14,    hTAS2R10 or hTAS2R4 bitter taste receptor activity, and where said    polypeptide is at least 80% identical to a polypeptide as shown in    SEQ ID NO: 2, 4, and 6, respectively;    comprising the steps:-   (1) contacting a bitter taste receptor encoded by said    polynucleotide or a host cell genetically engineered with said    polynucleotide or with a vector containing said polynucleotide to    express said bitter taste receptor with a potential antagonist; and-   (2) determining whether the potential antagonist inhibits the bitter    taste receptor activity,    wherein prior, concomitantly and/or after step (1) said bitter taste    receptor or said host cell is contacted with an agonist selected    from the group consisting of absinthin, artemorin, arglabin,    azathioprine, azepinon, benzoin, brucine, camphor, chlorhexidine,    N,N′-diethylthiourea, herbolid A, isohumulone, noscapine,    parthenolid, or arborescin agonistic derivatives or structurally    related agonists thereof for hTAS2R14; selected from the group    consisting of absinthin, artemorin, amarogentin, arglabin,    azathioprine, benzoin, camphor, cascarillin, papaverin, parthenolid,    picrotoxinin, arborescin or (−)-a-thujon and agonistic derivatives    or structurally related agonists thereof for hTAS2R10; or selected    from the group consisting of artemorin, amarogentin, azathioprine or    campor and agonistic derivatives or structurally related agonists    thereof for hTAS2R4.

In a further aspect the present invention provides a method forisolating an agonist of hTAS2R14, hTAS2R10 or hTAS2R4 bitter tastereceptor activity, wherein the bitter taste receptor is encoded by apolynucleotide selected from the group consisting of:

-   (a) polynucleotide encoding at least the mature form of the    polypeptide having the amino acid sequence as shown in SEQ ID NO: 2,    4, or 6;-   (b) polynucleotide having the coding nucleotide sequence as shown in    SEQ ID NO: 1, 3, or 5 encoding at least the mature form of the    polypeptide;-   (d) polynucleotide encoding a fragment or derivative of a    polypeptide encoded by a polynucleotide of any one of (a) to (b),    wherein in said derivative one or more amino acid residues are    conservatively substituted compared to said polypeptide, and said    fragment or derivative has hTAS2R14, hTAS2R10 and hTAS2R4 bitter    taste receptor activity, respectively;-   (d) polynucleotide which is an ortholog of the polynucleotide    sequences shown in SEQ ID NO: 1, 3, or 5 encoding at least the    mature form of the corresponding bitter taste receptor;-   (e) polynucleotide which encodes a polypeptide having hTAS2R14,    hTAS2R10 or hTAS2R4 bitter taste receptor activity, and where said    polypeptide is at least 80% identical to a polypeptide as shown in    SEQ ID NO: 2, 4, and 6, respectively;    comprising the steps:-   (1) contacting a bitter taste receptor encoded by said    polynucleotide or a host cell genetically engineered with said    polynucleotide or with a vector containing said polynucleotide to    express said bitter taste receptor with a potential agonist that is    structurally related to absinthin, artemorin, arglabin,    azathioprine, azepinon, benzoin, brucine, camphor, chlorhexidine,    N,N′-diethylthiourea, herbolid A, isohumulone, noscapine,    parthenolid, or arborescin for hTAS2R14; that is structurally    related to absinthin, artemorin, amarogentin, arglabin,    azathioprine, benzoin, camphor, cascarillin, papaverin, parthenolid,    picrotoxinin, arborescin or (−)-a-thujon for hTAS2R10; or that is    structurally related to artemorin, amarogentin, azathioprine or    campor for hTAS2R4; and-   (2) determining whether the potential agonist induces bitter taste    receptor activity.

The polynucleotide employed in both aspects of the present inventionencodes a polypeptide that still exhibits essentially the same activityas the mature hTAS2R14, hTAS2R10 or hTAS2R4 bitter taste receptor,respectively, i.e. has “bitter taste receptor activity”. Preferably thepolypeptide has at least 20% (e.g., at least: 20%; 30%; 40%; 50%; 60%;70%; 80%; 90%; 95%; 98%; 99%; 99.5%; or 100% or even more) of theactivity of the full-length mature hTAS2R14, hTAS2R10 and hTAS2R4,respectively. One preferred way of measuring hTAS2R14, hTAS2R10 andhTAS2R4 activity, respectively, is the ability to release intracellularcalcium in a heterologous cell expression system like, for example,(HEK293T/G16gust44) cells that stably expresses a chimeric G-proteinconsisting of Gα16 and 44 carboxylterminai amino acids of α-gustducin,in response to bitter tastants, which is dependent on the expression ofpolypeptides encoded by the polynucleotides of the present invention.The amount of intracellular calcium released can be monitored by, forexample, the in vitro FLIPR assay described herein but also by themeasurement of one of a variety of other parameters including, forexample, IP₃ or cAMP. Additional ways of measuring G-protein coupledreceptor activity are known in the art and comprise without limitationelectrophysiological methods, transcription assays, which measure, e.g.activation or repression of reporter genes which are coupled toregulatory sequences regulated via the respective G-protein coupledsignalling pathway, such reporter proteins comprise, e.g., CAT or LUC;assays measuring internalization of the receptor; or assays in frogmelanophore systems, in which pigment movement in melanophores is usedas a readout for the activity of adenylate cyclase or phospholipase C(PLC), which in turn are coupled via G-proteins to exogenously expressedreceptors (see, for example, McClintock T. S. et al. (1993) Anal.Biochem. 209: 298-305; McClintock T. S. and Lerner M. R. (1997) BrainRes. Brain, Res. Protoc. 2: 59-68, Potenza M N (1992) Pigment Cell Res.5: 372-328, and Potenza M. N. (1992) Anal. Biochem. 206: 315-322).

The term “potential antagonist”, comprises any perceivable chemicalsubstance or combination thereof in a non-purified, partially purifiedor purified state. The potential antagonist is selected on the basis ofits antagonizing behaviour. An “identified antagonist” of hTAS2R14,hTAS2R10 and hTAS2R4 bitter taste receptor activity, respectively, is asubstance which reduces the activity of hTAS2R14, hTAS2R10 or hTAS2R4stimulated by absinthin, artemorin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, chlorhexidine, N,N′-diethylthiourea, herbolidA, isohumulone, noscapine, parthenolid, or arborescin or structurallyrelated agonists thereof for hTAS2R14; absinthin, artemorin,amarogentin, arglabin, azathioprine, benzoin, camphor, cascarillin,papaverin, parthenolid, picrotoxinin, arborescin or (−)-a-thujon orstructurally related agonists thereof for hTAS2R10; or artemorin,amarogentin, azathioprine or campor or structurally related agoniststhereof for hTAS2R4 at least by 10% (e.g., at least: 10%, 15%; 20%; 30%;40%; 50%; 60%; 70%; 80%; 90%; 95%; 98%; 99%; 99.5%; or 100%) at the samemolar concentration. The extend of the lowering of the hTAS2R14,hTAS2R10 or hTAS2R4 bitter taste receptor activity, caused by theantagonist is determined in the presence of the respective agonist, e.g.absinthin, artemorin, arglabin, azathioprine, azepinon, benzoin,brucine, camphor, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, parthenolid, or arborescin or structurallyrelated agonists thereof for hTAS2R14; absinthin, artemorin,amarogentin, arglabin, azathioprine, benzoin, camphor, cascarillin,papaverin, parthenolid, picrotoxinin, arborescin or (−)-a-thujon orstructurally related agonists thereof for hTAS2R10; or artemorin,amarogentin, azathioprine or campor or structurally related agoniststhereof for hTAS2R4, which may be added prior, concomitantly or afteraddition of the antagonist. Preferably, the identified antagonist exertsthis activity, if present in the same molar concentration as absinthin,artemorin, amarogentin, arglabin, azathioprine, azepinon, benzoin,brucine, camphor, cascarillin, chlorhexidine, N,N′-diethylthiourea,herbolid A, isohumulone, noscapine, papaverin, parthenolid,picrotoxinin, arborescin or (−)-a-thujon or an agonist structurallyrelated to artemorin. In a preferred embodiment, the “potentialantagonist” is a compound structurally related to absinthin, artemorin,amarogentin, arglabin, azathioprine, azepinon, benzoin, brucine,camphor, cascarillin, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, papaverin, parthenolid, picrotoxinin, arborescinor (−)-a-thujon.

Preferably, the antagonist exerts its antagonizing action when it iscontacted prior, concomitantly or after, preferably concomitantly, tocontacting the hTAS2R14, hTAS2R10 and hTAS2R4 polypeptide, respectively,or the host cell genetically engineered with a polynucleotide encodinghTAS2R14, hTAS2R10 and hTAS2R4 polypeptide as defined above or with avector containing a polynucleotide as defined above to express hTAS2R14,hTAS2R10 and hTAS2R4 polypeptide, respectively, with absinthin,artemorin, amarogentin, arglabin, azathioprine, azepinon, benzoin,brucine, camphor, cascarillin, chlorhexidine, N,N′-diethylthiourea,herbolid A, isohumulone, noscapine, papaverin, parthenolid,picrotoxinin, arborescin or (−)-a-thujon or an agonist structurallyrelated to absinthin, artemorin, amarogentin, arglabin, azathioprine,azepinon, benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin or (−)-a-thujon. Preferably, ifcontacted at the same molar concentration as absinthin, artemorin,amarogentin, arglabin, azathioprine, azepinon, benzoin, brucine,camphor, cascarillin, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, papaverin, parthenolid, picrotoxinin, arborescinor (−)-a-thujon or the structurally related agonist.

The term “potential agonist”, comprises substances structurally relatedto absinthin, artemorin, amarogentin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin or (−)-a-thujon in a non-purified,partially purified or purified state. The potential agonist is selectedon the basis of its hTAS2R14, hTAS2R10 and hTAS2R4 bitter taste receptoractivity stimulating behaviour. An “identified agonist” stimulateshTAS2R14, hTAS2R10 and hTAS2R4 bitter taste receptor activity,respectively, to at least 10% (e.g., at least: 10%, 30%, 50%, 80%, 100%,200%, 300%, 500%, 1,000%, 10,000%) of the activity elicited byabsinthin, artemorin, amarogentin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin and (−)—a-thujon, respectively.Preferably, the identified agonist exerts this activity, if present atthe same molar concentration as absinthin, artemorin, amarogentin,arglabin, azathioprine, azepinon, benzoin, brucine, camphor,cascarillin, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, papaverin, parthenolid, picrotoxinin, arborescinor (−)-a-thujon.

The hTAS2R14, hTAS2R10 and hTAS2R4 polynucleotide molecules,respectively, usable in the method of the present invention can be DNA,cDNA, genomic DNA, synthetic DNA, or RNA, and can be double-stranded orsingle-stranded, the sense and/or an antisense strand. Segments of thesemolecules are also considered within the scope of the invention, and canbe produced by, for example, the polymerase chain reaction (PCR) orgenerated by treatment with one or more restriction endonucleases. Aribonucleic acid (RNA) molecule can be produced by in vitrotranscription.

The polynucleotide molecules useable in the method of the presentinvention can contain naturally occurring sequences, or sequences thatdiffer from those that occur naturally, but, due to the degeneracy ofthe genetic code, encode the same polypeptide (for example, thepolypeptide with SEQ ID NO: 2, 4, or 6). In addition, these nucleic acidmolecules are not limited to coding sequences, e.g., they can includesome or all of the non-coding sequences that lie upstream or downstreamfrom a coding sequence.

The polynucleotide molecules of the invention can be synthesized invitro (for example, by phosphoramidite-based synthesis) or obtained froma cell, such as the cell of a bacteria or a mammal. The nucleic acidscan be those of a human but also include orthologous polynucleotidesderived from a non-human primate, mouse, rat, guinea pig, cow, sheep,horse, pig, rabbit, dog, or cat as long as they fulfil the criteria setout above. Combinations or modifications of the polynucleotides withinthese types of nucleic acids are also encompassed. Means to identifyorthologous polynucleotide molecules of the invention are available to aperson of skill and comprise the use of BLAST searches (see below) anddatabase mining of databases such as the EMBL, NCBI and other databasescomprising polynucleotides and amino acid sequences.

In addition, the polynucleotides useable in the method of the presentinvention can encompass segments that are not found as such in thenatural state. Thus, the invention encompasses recombinant nucleic acidmolecules incorporated into a vector (for example, a plasmid or viralvector) or into the genome of a heterologous cell (or the genome of ahomologous cell, at a position other than the natural chromosomallocation). Recombinant nucleic acid molecules and uses therefore arediscussed further below.

In certain preferred embodiments the method of the present inventionuses isolated nucleic acid molecules which are at least 50% (or 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) identical to: (a) anucleic acid molecule that encodes the polypeptide of SEQ ID NO: 2, 4,or 6; (b) the polynucleotide sequence of SEQ ID NO: 1, 3, or 5 and (c) anucleic acid molecule which includes a segment of at least 30 (e.g., atleast 30, 40, 50, 60, 80, 100, 125, 150, 175, 200, 250, 300, 400, 500,600, 700, 800, 850, and 900) contiguous polynucleotides of SEQ ID NO: 1,3 and 5, respectively, in as long as these nucleic acid molecules encodea polypeptide having hTAS2R14, hTAS2R10 and hTAS2R4 bitter tastereceptor activity, respectively

The determination of percent identity between two sequences isaccomplished using the mathematical algorithm of Karlin and Altschul(1993) Proc. Natl. Acad. ScI USA 90: 5873-5877. Such an algorithm isincorporated into the BLASTN and BLASTP programs of Altschul et al.(1990) J. MoI. Biol. 215: 403-410. BLAST polynucleotide searches areperformed with the BLASTN program, score=100, word length=12, to obtainpolynucleotide sequences homologous to hTAS2R14, hTAS2R10 or hTAS2R4encoding nucleic acids. BLAST protein searches are performed with theBLASTP program, score=50, wordlength=3, to obtain amino acid sequenceshomologous to the hTAS2R14, hTAS2R10 and hTAS2R4 polypeptide,respectively. To obtain gapped alignments for comparative purposes,Gapped BLAST is utilized as described in Altschul et al. (1997) NucleicAcids Res. 25: 3389-3402. When utilizing BLAST and Gapped BLASTprograms, the default parameters of the respective programs are used.

Hybridization can also be used as a measure of homology between twonucleic acid sequences. A nucleic acid sequence encoding hTAS2R14,hTAS2R10 or hTAS2R4, or a portion thereof, can be used as ahybridization probe according to standard hybridization techniques. Thehybridization of a hTAS2R14, hTAS2R10 or hTAS2R4 probe to DNA or RNAfrom a test source (e.g., a mammalian cell) is an indication of thepresence of the hTAS2R14, hTAS2R10 or hTAS2R4 DNA or RNA in the testsource. Hybridization conditions are known to those skilled in the artand can be found, for example, in Current Protocols in MolecularBiology, John Wiley & Sons, N.Y., 6.3.1-6.3.6, 1991. Moderatehybridization conditions are defined as equivalent to hybridization in2× sodium chloride/sodium citrate (SSC) at 30° C., followed by a wash in1×SSC, 0.1% SDS at 50° C. Highly stringent conditions are defined asequivalent to hybridization in 6× sodium chloride/sodium citrate (SSC)at 45° C., followed by a wash in 0.2×SSC, 0.1% SDS at 65° C.

The polynucleotides or proteins useable in the method of the presentinvention can be comprised in a vector containing the polynucleotide(s)or a protein encoded by above-mentioned polynucleotide. The term“vector” refers to a protein or a polynucleotide or a mixture thereofwhich is capable of being introduced or of introducing the proteinsand/or nucleic acid comprised therein into a cell. It is preferred thatthe proteins encoded by the introduced polynucleotide are expressedwithin the cell upon introduction of the vector.

In a preferred embodiment a vector useable in the method of the presentinvention comprises plasmids, phagemids, phages, cosmids, artificialmammalian chromosomes, knock-out or knock-in constructs, viruses, inparticular adenoviruses, vaccinia viruses, attenuated vaccinia viruses,canary pox viruses, lentivirus (Chang, U. and Gay, E. E. (2001) Curr.Gene Therap. 1: 237-251), herpes viruses, in particular Herpes simplexvirus (HSV-I, Carlezon, W. A. et al. (2000) Crit. Rev. Neurobiol. 14:47-67), baculovirus, retrovirus, adeno-associated-virus (AAV, Carter, PJ. and Samulski, R J. (2000) J. MoI. Med. 6:17-27), rhinovirus, humanimmune deficiency virus (HIV), filovirus and engineered versions thereof(see, for example, Cobinger G. P. et al. (2001) Nat. Biotechnol.19:225-30), virosomes, “naked” DNA liposomes, and nucleic acid coatedparticles, in particular gold spheres. Particularly preferred are viralvectors like adenoviral vectors or retroviral vectors (Lindemann et al.(1997) MoI. Med. 3: 466-76 and Springer et al. (1998) MoI. Cell. 2:549-58). Liposomes are usually small unilamellar or multilamellarvesicles made of cationic, neutral and/or anionic lipids, for example,by ultrasound treatment of liposomal suspensions. The DNA can, forexample, be ionically bound to the surface of the liposomes orinternally enclosed in the liposome. Suitable lipid mixtures are knownin the art and comprise, for example, DOTMA (1,2-Dioleyloxpropyl-3-trimethylammoniumbromid) and DOPE(Dioleoyl-phosphatidylethanolamin) which both have been used on avariety of cell lines.

Nucleic acid coated particles are another means for the introduction ofnucleic acids into cells using so called “gene guns”, which allow themechanical introduction of particles into cells. Preferably theparticles itself are inert, and therefore, are in a preferred embodimentmade out of gold spheres.

In a further aspect polynucleotides useable in the method of the presentinvention are operatively linked to expression control sequencesallowing expression in prokaryotic and/or eukaryotic host cells. Thetranscriptional/translational regulatory elements referred to aboveinclude but are not limited to inducible and non-inducible,constitutive, cell cycle regulated, metabolically regulated promoters,enhancers, operators, silencers, repressors and other elements that areknown to those skilled in the art and that drive or otherwise regulategene expression. Such regulatory elements include but are not limited toregulatory elements directing constitutive expression like, for example,promoters transcribed by RNA polymerase III like, e.g. promoters for thesnRNA U6 or scRNA 7SK gene, the cytomegalovirus hCMV immediate earlygene, the early or late promoters of SV40 adenovirus, viral promoter andactivator sequences derived from, e.g. NBV, HCV, HSV, HPV, EBV, HTLV,MMTV or HIV; which allow inducible expression like, for example, CUP-Ipromoter, the tet-repressor as employed, for example, in the tet-on ortet-off systems, the lac system, the trp, system; regulatory elementsdirecting tissue specific expression, preferably taste bud specificexpression, e.g. PLCB2 promoter or gustducin promoter, regulatoryelements directing cell cycle specific expression like, for example,cdc2, cdc25C or cyclin A; or the TAC system, the TRC system, the majoroperator and promoter regions of phage A, the control regions of fd coatprotein, the promoter for 3-phosphoglycerate kinase, the promoters ofacid phosphatase, and the promoters of the yeast α- or a-mating factors.

As used herein, “genetically engineered” means that the host cell istransgenic for the polynucleotide or vector containing thepolynucleotide.

A polypeptide encoding a “mature form” of a protein or polypeptide meansthat said protein or polypeptide contains all polypeptide elements thatallow it to undergo some or all potential post- or cotranslationalprocesses such as proteolytic processing, phosphorylation, lipidationand the like comprised in the state of the art such that saidpolypeptide or protein can correctly fold and carry out part or all ofits wildtype function once it reaches its “mature form”.

As used herein, “operatively linked” means incorporated into a geneticconstruct so that expression control sequences effectively controlexpression of a coding sequence of interest.

Similarly, the polynucleotides useable in the method of the presentinvention can form part of a hybrid gene encoding additional polypeptidesequences, for example, a sequence that functions as a marker orreporter. Examples of marker and reporter genes include β-lactamase,chloramphenicol acetyltransferase (CAT), adenosine deaminase (ADA),aminoglycoside phosphotransferase (neo^(r), G418^(r)), dihydrofolatereductase (DHFR), hygromycin-B-phosphotransferase (HPH), thymidinekinase (TK), lacZ (encoding β-galactosidase), and xanthine guaninephosphoribosyl-transferase (XGPRT). As with many of the standardprocedures associated with the practice of the method of the invention,skilled artisans will be aware of additional useful reagents, forexample, additional sequences that can serve the function of a marker orreporter.

The method of the present invention may also use hybrid polypeptides orpolynucleotides encoding them. In general a hybrid polypeptide willinclude a first portion and a second portion; the first portion beingone or more hTAS2R14, hTAS2R10 or hTAS2R4 polypeptide and the secondportion being, for example, the reporter(s) described above or an Igconstant region or part of an Ig constant region, e.g., the CH2 and CH3domains of IgG2a heavy chain. Other hybrids could include an antigenictag or His tag to facilitate purification and/or detection. Recombinantnucleic acid molecules can also contain a polynucleotide sequenceencoding the hTAS2R14, hTAS2R10 or hTAS2R4 polypeptide operativelylinked to a heterologous signal sequence. Such signal sequences candirect the protein to different compartments within the cell and arewell known to someone of skill in the art. A preferred signal sequenceis a sequence that facilitates secretion of the resulting protein.

Another aspect of the present invention is the use of a host cellgenetically engineered with a polynucleotide or a vector as outlinedabove. The host cells that may be used in the method of the presentinvention include but are not limited to prokaryotic cells such asbacteria (for example, E. coli and B. subtilis), which can betransformed with, for example, recombinant bacteriophage DNA, plasmidDNA, or cosmid DNA expression vectors containing the polynucleotidemolecules of the invention; simple eukaryotic cells like yeast (forexample, Saccharomyces and Pichia), which can be transformed with, forexample, recombinant yeast expression vectors containing thepolynucleotide molecule of the invention; insect cell systems like, forexample, Sf9 or Hi5 cells, which can be infected with, for example,recombinant virus expression vectors (for example, baculovirus)containing the polynucleotide molecules; amphibian cells, e.g. Xenopusoocytes, which can be injected with, for example, plasmids; plant cellsystems, which can be infected with, for example, recombinant virusexpression vectors (for example, cauliflower mosaic virus (CaMV) ortobacco mosaic virus (TMV)) or transformed with recombinant plasmidexpression vectors (for example, Ti plasmid) containing a hTAS2R14,hTAS2R10 or hTAS2R4 polynucleotide sequence; or mammalian cell systems(for example, COS, CHO, BHK, HEK293, VERO, HeLa, MDCK, Wi38, and NIH 3T3cells), which can be transformed with recombinant expression constructscontaining, for example, promoters derived, for example, from the genomeof mammalian cells (for example, the metallothionein promoter) frommammalian viruses (for example, the adenovirus late promoter and thevaccinia virus 7.5K promoter) or from bacterial cells (for example, thetet-repressor binding is employed in the tet-on and tet-off systems).Also useful as host cells are primary or secondary cells obtaineddirectly from a mammal and transfected with a plasmid vector or infectedwith a viral vector. Depending on the host cell and the respectivevector used to introduce the polynucleotide of the invention thepolynucleotide can integrate, for example, into the chromosome or themitochondrial DNA or can be maintained extrachromosomally like, forexample, episomally or can be only transiently comprised in the cells.

In a preferred embodiment, the hTAS2R14, hTAS2R10 or hTAS2R4 expressedby such cells are functional and have bitter taste receptor activity,i.e., upon binding to one or more bitter molecules they trigger anactivation pathway in the cell. The cells are preferably mammalian(e.g., human, non-human primate, horse, bovine, sheep, pig, dog, cat,goat, rabbit, mouse, rat, guinea pig, hamster, or gerbil) cells, insectcells, bacterial cells, or fungal (including yeast) cells. Thepolypeptides useable in the method of the invention include all thosedisclosed herein and functional fragments of these polypeptides. Theterms “polypeptide” and “protein” are used interchangeably and mean anypeptide-linked chain of amino acids, regardless of length orpost-translational modification. As used herein, a functional fragmentof the hTAS2R14, hTAS2R10 or hTAS2R4 is a fragment of the hTAS2R14,hTAS2R10 or hTAS2R4 that is shorter than the full-length hTAS2R14,hTAS2R10 or hTAS2R4 but that has at least 20% (e.g., at least: 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 100%, 150%, 200%,500%, 1000%, 10000% or even more) of the ability of the full-lengthhTAS2R14, hTAS2R10 or hTAS2R4 to be stimulated by one of the bittersubstances identified herein. Binding assays and bitter substances aredescribed in more detail herein below. The polypeptides can also includefusion proteins that contain either a full-length hTAS2R14, hTAS2R10 orhTAS2R4 polypeptide or a functional fragment of it fused to an unrelatedamino acid sequence. The unrelated sequences can add further functionaldomains or signal peptides.

The polypeptides can be any of those described above but with not morethan 50 (e.g., not more than: 50, 45, 40, 35, 30, 25, 20, 15, 14, 13,12, 11, 10, nine, eight, seven, six, five, four, three, two, or one)conservative substitutions. Conservative substitutions typically includesubstitutions within the following groups: glycine and alanine; valine,isoleucine, and leucine; aspartic acid and glutamic acid; asparagine,glutamine, serine and threonine; lysine, histidine and arginine; andphenylalanine and tyrosine. All that is required of a polypeptide havingone or more conservative substitutions is that it has at least 20%(e.g., at least: 20%; 30%; 40%; 50%; 60%; 70%; 80%; 90%; 95%; 98%; 99%;99.5%; 100%, 150%, 200%, 500%, 1000%, 10000% or even more) of theability of the full-length hTAS2R14, hTAS2R10 or hTAS2R4 to bestimulated by the respective agonist.

Polypeptides and fragments of the polypeptides useable in the method ofthe present invention can be modified, for example, for in vivo use bythe addition of blocking agents, at the amino- and/or carboxyl-terminalends, to facilitate survival of the relevant polypeptide in vivo. Thiscan be useful in those situations in which the peptide termini tend tobe degraded by proteases prior to cellular uptake. Such blocking agentscan include, without limitation, additional related or unrelated peptidesequences that can be attached to the amino and/or carboxyl terminalresidues of the peptide to be administered. This can be done eitherchemically during the synthesis of the peptide or by recombinant DNAtechnology by methods familiar to artisans of average skill. Theantagonists or agonists of the bitter taste receptors identified hereinare of great importance for specific stimulation of a given bitter tastereceptor and identification of substances that antagonize it,respectively.

The term “contacting” in the context of the present invention means anyinteraction between the antagonist and/or agonist with the polypeptideor the host cell, whereby any of the at least two components can beindependently of each other in a liquid phase, for example in solution,or in suspension or can be bound to a solid phase, for example, in theform of an essentially planar surface or in the form of particles, beadsor the like, in a preferred embodiment a multitude of differentcompounds are immobilized on a solid surface like, for example, on acompound library chip and the protein of the present invention issubsequently contacted with such a chip, in another preferred embodimentthe host cells are genetically engineered with a polynucleotide encodinghTAS2R14, hTAS2R10 or hTAS2R4 or with a vector containing such apolynucleotide, express the hTAS2R¹⁴, hTAS2R¹⁰ or hTAS2R⁴ bitter tastereceptor at the cell surface and are contacted separately in smallcontainers, e.g., micro-titre plates, with various compounds.

As used herein, the term “isolating” an agonist or antagonist refers tothe process of selecting, identifying, isolating or evolving an agonistor antagonist out of a group of at least two different potentialagonists or potential antagonists whereby the said selected, identified,isolated or evolved agonist or antagonist exhibits preferred featurescompared with the other agonist or antagonists such as, for example,stronger modulation, e.g. activation or inhibition, of receptoractivation and/or longer or shorter lasting modulation, e.g. activationor inhibition, of receptor activation.

As a further step after measuring the antagonizing effect of a potentialantagonist and after having measured the decrease of bitter taste for atleast two different potential antagonists at least one potentialantagonist can be selected, for example, on grounds of the detecteddecrease of intracellular release of calcium, if compared to contactingwith the known agonist alone.

In a preferred embodiment of either method of the present invention thepotential agonist or potential antagonist that is employed in theidentification process is structurally related to absinthin, arglabin,arborescin, artemorin, noscapine, or parthenolide and has a structureaccording to formula (I)

wherein

-   R¹ and R² together form a cycloalkyl, preferably C₃-C₁₄-cycloalkyl,    e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or    C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,    spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl,    spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,    spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,    bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,    bicyclo[4.2.0]octyl, bicyclo[5.3.0]decyl, octahydro-pentalenyl,    octahydro-indenyl, decahydro-azulenyl, adamantly, or    decahydro-naphthalenyl; heterocycloalkyl, preferably    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₋₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, or decahydro-quinazolinyl; an alicyclic    system, preferably C₃-C₁₄-alicyclic system, e.g. C₃, C₄, C₅, C₆, C₇,    C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-alicyclic system, in particular    cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,    cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl,    spiro[3,3]heptenyl, spiro[3,4]octenyl, spiro[4,3]octenyl,    spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl,    spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl,    bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl,    bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl,    bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, bicyclo[5.3.0]decenyl,    hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or    octahydro-naphthalenyl, or a derivative thereof, wherein 1, 2 or 3    carbon atoms are replaced by a heteroatom each independently    selected from the group consisting of nitrogen, sulphur, or oxygen;    aryl, in particular phenyl, naphthalenyl or anthracenyl; or    heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;    preferably decahydro-naphthalenyl, cyclodecyl,    octahydro-naphthalenyl, or cyclodecenyl; optionally substituted; R³    is H, OH, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅,    or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,    iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆    alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in    particular C₁-C₆ alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    preferably C₁-C₆ alkyl, more preferably methyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,

C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particularcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl,bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, bicyclo[5.3.0]decyl,octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly,or decahydro-naphthalenyl; heterocycloalkyl, preferablyC₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,decahydro-quinoxalinyl, or decahydro-quinazolinyl; an alicyclic system,preferably C₃-C₁₄-alicyclic system, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-alicyclic system, in particular cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl,cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl, spiro[3,4]octenyl,spiro[4,3]octenyl, spiro[3,5]nonenyl, spiro[5,3]nonenyl,spiro[3,6]decenyl, spiro[6,3]decenyl, spiro[4,5]decenyl,spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl,bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl,bicyclo[4.2.0]octenyl, bicyclo[5.3.0]decenyl, hexahydro-pentalenyl,hexahydro-indenyl, octahydro-azulenyl, or octahydro-naphthalenyl, or aderivative thereof, wherein 1, 2 or 3 carbon atoms are replaced by aheteroatom each independently selected from the group consisting ofnitrogen, sulphur, or oxygen; aryl, in particular phenyl, naphthalenylor anthracenyl; or heteroaryl, in particular furanyl, thienyl, oxazolyl,isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl,2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or1,2,4-benzotriazinyl; preferably decahydro-naphthalenyl, cyclodecyl,octahydro-naphthalenyl, or cyclodecenyl; optionally substituted;

-   X is O or S; preferably O;-   Y is O or NH or S; preferably O; and    the dashed bond may present or not, preferably the dashed bond is    present.

In a preferred embodiment of the method of the present invention thering system formed by R¹ and R² is

-   (i) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,    cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    bicyclo[5.3.0]decyl, octahydro-pentalenyl, octahydro-indenyl,    decahydro-azulenyl, adamantly, or decahydro-naphthalenyl; optionally    substituted 1 to 14 times, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,    12, 13, or 14 times, depending on the number of available valences    with a substituent which is in each instance independently selected    from the group consisting of halogen, in particular F, Cl, Br or I;    —NO₂; —CN; —OR⁶; —NR⁶R⁷; —COOR⁶; —CONR⁶R⁷; —NR⁸COR⁹; —NR⁸COR⁹;    —NR⁸CONR⁶R⁷; —NR⁹SO₂A; —COR⁶; —SO₂NR⁶R⁷; —OOCR⁸; —CR⁸R⁹OH; R⁸OH; and    -A; or two substituents on adjacent carbon atoms form together with    an oxygen atom an epoxy group or a cycloalkyl, cycloheteroalkyl,    alicyclic system, aryl or heteroaryl;    -   R⁶ and R⁷ is each independently selected from the group        consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in        particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,        cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,        spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,        spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,        spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,1′-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in        particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        aralkyl, preferably C₁-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or        C₆ aralkyl; or together form a heteroaryl, in particular,        oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,        pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,        isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,        pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,        1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, isoindolyl,        1H-indazolyl, benzimidazolyl, indoxazinyl, 2,1-benzisoxazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;    -   R⁸ and R⁹ is each independently selected from the group        consisting of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃,        C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in        particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,        spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in        particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,        preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,        iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular        phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆        aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        —NR⁶R⁷;    -   A is selected from the group consisting of alkyl, in particular        C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably        methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,        pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁,        C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl,        1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,        1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅,        or C₆ alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.        C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,        cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy,        in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆        alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,        butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;        alkoxyalkyl, in particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g.        methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,        ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or        propoxypropyl; heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl,        e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,        1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7        diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8        diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6        diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7        diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7        diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7        diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic        system, which may comprise one or more heteroatoms, e.g. 1, 2,        3, or 4, preferably selected from the group consisting of O, S,        or N; in particular 1,2-dihydropyridinyl,        1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,        1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl,        in particular phenyl, naphthalenyl or anthracenyl; and        heteroaryl, in particular furanyl, thienyl, oxazolyl,        isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl,        imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;-   (ii) piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8    diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6    diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7    diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8    diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8    diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8    diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,    1-aza-7,11-dioxo-spiro[5,5]undecyl, 1,4-diazabicyclo[2.2.2]oct-2-yl,    tetrahydrofuran-2-yl, tetrahydrofuranyl, tetrahydrothienyl,    tetrahydrothienyl, piperazinyl, decahydro-quinolinyl,    decahydro-isoquinolinyl, decahydro-quinoxalinyl, or    decahydro-quinazolinyl; optionally substituted 1 to 14 times, i.e.    1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 times, depending on    the number of available valences with a substituent which is in each    instance independently selected from the group consisting of    halogen, in particular F, Cl, Br or I; —NO₂; —CN; —OR⁶; —NR⁶R⁷;    —COOR⁶; —CONR⁶R⁷; —NR⁸COR⁹; —NR⁸COR⁹; —NR⁸CONR⁶R⁷; —NR⁹SO₂A; —COR⁶;    —SO₂NR⁶R⁷; —OOCR⁸; —CR⁸R⁹OH; R⁸OH; and -A or two substituents on    adjacent carbon or heteroatoms atoms—as the case may be—form    together a cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or    heteroaryl;    -   R⁶ and R⁷ is each independently selected from the group        consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in        particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,        cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,        spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,        spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,        spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in        particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        aralkyl, preferably C₁-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or        C₆ aralkyl; or together form a heteroaryl, in particular,        oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,        pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,        isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,        pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,        1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, isoindolyl,        1H-indazolyl, benzimidazolyl, indoxazinyl, 2,1-benzisoxazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;    -   R⁸ and R⁹ is each independently selected from the group        consisting of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃,        C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in        particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,        spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in        particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,        preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,        iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular        phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆        aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        —NR⁶R⁷;    -   A is selected from the group consisting of alkyl, in particular        C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably        methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,        pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁,        C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl,        1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,        1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅,        or C₆ alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.        C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,        cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy,        in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆        alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,        butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;        alkoxyalkyl, in particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g.        methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,        ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or        propoxypropyl; heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl,        e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,        1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7        diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8        diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6        diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7        diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7        diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7        diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic        system, which may comprise one or more heteroatoms, e.g. 1, 2,        3, or 4, preferably selected from the group consisting of O, S,        or N; in particular 1,2-dihydropyridinyl,        1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,        1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl,        in particular phenyl, naphthalenyl or anthracenyl; and        heteroaryl, in particular furanyl, thienyl, oxazolyl,        isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl,        imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;-   (iii) cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,    cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl,    cyclodecdienyl, spiro[3,3]heptenyl, spiro[3,4]octenyl,    spiro[4,3]octenyl, spiro[3,5]nonenyl, spiro[5,3]nonenyl,    spiro[3,6]decenyl, spiro[6,3]decenyl, spiro[4,5]decenyl,    spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl,    bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl,    bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, bicyclo[5.3.0]decenyl,    hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or    octahydro-naphthalenyl, or a derivative thereof, wherein 1, 2 or 3    carbon atoms are replaced by a heteroatom each independently    selected from the group consisting of nitrogen, sulphur, or oxygen;    optionally substituted 1 to 14 times, i.e. 1, 2, 3, 4, 5, 6, 7, 8,    9, 10, 11, 12, 13, or 14 times, depending on the number of available    valences with a substituent which is in each instance independently    selected from the group consisting of halogen, in particular F, Cl,    Br or I; —NO₂; —CN; —OR⁶; —NR⁶R⁷; —COOR⁶; —CONR⁶R⁷; —NR⁸COR⁹;    —NR⁸COR⁹; —NR⁸CONR⁶R⁷; —NR⁹SO₂A; —COR⁶; —SO₂NR⁶R⁷; —OOCR⁸; —CR⁸R⁹OH;    R⁸OH; and -A or two substituents on adjacent carbon or heteroatoms    atoms—as the case may be—form together with an oxygen atom an epoxy    group or a cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or    heteroaryl;    -   R⁶ and R⁷ is each independently selected from the group        consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in        particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,        cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,        spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,        spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,        spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in        particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        aralkyl, preferably C₁-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or        C₆ aralkyl; or together form a heteroaryl, in particular,        oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,        pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,        isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,        pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,        1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, isoindolyl,        1H-indazolyl, benzimidazolyl, indoxazinyl, 2,1-benzisoxazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted; R⁸ and R⁹ is each independently selected        from the group consisting of hydrogen; alkyl, in particular        C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably        methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,        pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂,        C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl,        2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl,        2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g.        C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particular        C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,        C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,        cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,        spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,        spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,        spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in        particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,        preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,        iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular        phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆        aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        —NR⁶R⁷;    -   A is selected from the group consisting of alkyl, in particular        C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably        methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,        pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁,        C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl,        1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,        1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅,        or C₆ alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.        C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,        cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy,        in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆        alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,        butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;        alkoxyalkyl, in particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g.        methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,        ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or        propoxypropyl; heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl,        e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,        1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7        diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8        diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6        diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7        diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7        diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7        diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic        system, which may comprise one or more heteroatoms, e.g. 1, 2,        3, or 4, preferably selected from the group consisting of O, S,        or N; in particular 1,2-dihydropyridinyl,        1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,        1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl,        in particular phenyl, naphthalenyl or anthracenyl; and        heteroaryl, in particular furanyl, thienyl, oxazolyl,        isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl,        imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;-   (iv) phenyl, naphthalenyl or anthracenyl;    -   optionally substituted 1 to 9 times, i.e. 1, 2, 3, 4, 5, 6, 7,        8, or 9 times, depending on the number of available valences        with a substituent which is in each instance independently        selected from the group consisting of halogen, in particular F,        Cl, Br or I; —NO₂; —CN; —OR⁶; —NR⁶R⁷; —COOR⁶; —CONR⁶R⁷;        —NR⁸COR⁹; —NR⁸COR⁹; —NR⁸CONR⁶R⁷; —NR⁹SO₂A; —COR⁶—SO₂NR⁶R⁷;        —OOCR⁸; —CR⁸R⁹OH; R⁸OH; and -A or two substituents on adjacent        carbon atoms together form an alicyclic system, aryl or        heteroaryl;    -   R⁶ and R⁷ is each independently selected from the group        consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in        particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,        cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,        spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,        spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,        spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in        particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        aralkyl, preferably C₁-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or        C₆ aralkyl; or together form a heteroaryl, in particular,        oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,        pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,        isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,        pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,        1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, isoindolyl,        1H-indazolyl, benzimidazolyl, indoxazinyl, 2,1-benzisoxazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;    -   R⁸ and R⁹ is each independently selected from the group        consisting of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃,        C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in        particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,        spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in        particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,        preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,        iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular        phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆        aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        —NR⁶R⁷;    -   A is selected from the group consisting of alkyl, in particular        C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably        methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,        pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁,        C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl,        1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,        1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅,        or C₆ alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.        C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,        cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy,        in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆        alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,        butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;        alkoxyalkyl, in particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g.        methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,        ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or        propoxypropyl; heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl,        e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,        1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7        diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8        diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6        diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7        diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7        diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7        diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic        system, which may comprise one or more heteroatoms, e.g. 1, 2,        3, or 4, preferably selected from the group consisting of O, S,        or N; in particular 1,2-dihydropyridinyl,        1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,        1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl,        in particular phenyl, naphthalenyl or anthracenyl; and        heteroaryl, in particular furanyl, thienyl, oxazolyl,        isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl,        imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;    -   or-   (v) furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, and    1,2,4-benzotriazinyl; optionally substituted 1 to 14 times, i.e. 1,    2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 times, depending on    the number of available valences with a substituent which is in each    instance independently selected from the group consisting of    halogen, in particular F, Cl, Br or I; —NO₂; —CN; —OR⁶; —NR⁶R⁷;    —COOR⁶; —CONR⁶R⁷; —NR⁸COR⁹; —NR⁸COR⁹; —NR⁸CONR⁶R⁷; —NR⁹SO₂A; —COR⁶;    —OOCR⁸; —CR⁸R⁹OH; R⁸OH; and -A or two substituents on adjacent    carbon or heteroatoms atoms—as the case may be—form together with an    oxygen atom an epoxy group or an alicyclic system, aryl or    heteroaryl;    -   R⁶ and R⁷ is each independently selected from the group        consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in        particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,        cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,        spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,        spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,        spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₂, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in        particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        aralkyl, preferably C₁-C₆ aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or        C₆ aralkyl; or together form a heteroaryl, in particular,        oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,        pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,        isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,        pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,        1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, isoindolyl,        1H-indazolyl, benzimidazolyl, indoxazinyl, 2,1-benzisoxazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted;    -   R⁸ and R⁹ is each independently selected from the group        consisting of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g.        C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,        propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;        alkenyl, in particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,        1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;        alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆        alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃,        C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in        particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,        spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl;        heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅,        C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in        particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8        diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6        diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7        diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8        diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8        diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8        diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,        1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in        particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,        preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,        iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular        phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆        aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in        particular furanyl, thienyl, oxazolyl, isoxazolyl,        1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and        —NR⁶R⁷;    -   A is selected from the group consisting of alkyl, in particular        C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably        methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,        pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁,        C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl,        1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,        1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅,        or C₆ alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.        C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,        cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,        spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,        spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,        bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,        bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,        bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,        decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy,        in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆        alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,        butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;        alkoxyalkyl, in particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g.        methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,        ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or        propoxypropyl; heterocycloalkyl, e.g. C₃-C₁₄-heterocycloalkyl,        e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or        C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,        1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7        diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8        diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6        diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7        diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7        diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7        diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,        1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,        tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,        piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,        decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic        system, which may comprise one or more heteroatoms, e.g. 1, 2,        3, or 4, preferably selected from the group consisting of O, S,        or N; in particular 1,2-dihydropyridinyl,        1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,        1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl,        in particular phenyl, naphthalenyl or anthracenyl; and        heteroaryl, in particular furanyl, thienyl, oxazolyl,        isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl,        imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,        1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,        pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,        1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,        benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,        benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,        1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,        quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,        quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;        optionally substituted.

In a preferred method of the present invention the potential agonist orpotential antagonist structurally related to artemorin or parthenolidehas a structure according to formula (II)

wherein

-   R³ is H, OH, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in    particular C₁-C₆ alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    preferably C₁-C₆ alkyl, more preferably methyl; optionally    substituted;-   R⁴ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together with an oxygen atom an epoxy group or a    cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or heteroaryl;-   R⁵ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;-   A is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted;-   m is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; preferably    1;-   n is an integer from 0 to 8, i.e. 0, 1, 2, 3, 4, 5, 6, 7, or 8,    preferably 2;-   X is O or S; preferably O;-   Y is O or NH or S; preferably O; and    the cyclodecyl may contain one, two or three double bonds,    preferably one double bond and the dashed bond may be present or    not, preferably the dashed bond is present.

It is further preferred that at least two substituents R⁴ and/or R⁵ havethe meaning -A.

In a further preferred embodiment the potential agonist or potentialantagonist structurally related to artemorin has a structure accordingto formula (III)

wherein

-   R³ is H, OH, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in    particular C₁-C₆ alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    preferably C₁-C₆ alkyl, more preferably methyl; optionally    substituted;-   R⁴ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A;-   R⁵ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;

A is selected from the group consisting of alkyl, in particular C₁-C₆alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particularC₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl,spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy, inparticular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particularC₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g.C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl,decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl,decahydro-quinazolinyl; an alicyclic system, which may comprise one ormore heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the groupconsisting of O, S, or N; in particular 1,2-dihydropyridinyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, inparticular phenyl, naphthalenyl or anthracenyl; and heteroaryl, inparticular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; alkyl, in particularC₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl,ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; morepreferably methyl; optionally substituted; B is selected from the groupconsisting of alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅,or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₆alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl,ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅,C₆, C₂, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particularcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl,bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl,octahydro-indenyl, decahydro-azulenyl, adamantly,decahydro-naphthalenyl; alkoxy, in particular C₁-C₆ alkoxy, e.g. C₁, C₂,C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy,iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;alkoxyalkyl, in particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl,ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g.C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl,decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl,decahydro-quinazolinyl; an alicyclic system, which may comprise one ormore heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the groupconsisting of O, S, or N; in particular 1,2-dihydropyridinyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, inparticular phenyl, naphthalenyl or anthracenyl; and heteroaryl, inparticular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; preferably alkyl, inparticular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferablymethyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, orC₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; morepreferably methenyl; optionally substituted;

-   m is an integer from 0 to 4, i.e. 0, 1, 2, 3 or 4, preferably 1;-   n is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5 or 6, preferably    0 or 1;-   X is O or S; preferably O;-   Y is O or NH or S; preferably O; and    the dashed bond may be present or not, preferably the dashed bond is    present.

In a preferred method of the present invention the potential agonist orpotential antagonist structurally related to aborescin, absinthin, orarglabin has a structure according to formula (IV)

wherein

-   R³ is H, OH, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in    particular C₁-C₆ alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    preferably C₁-C₆ alkyl, more preferably methyl; optionally    substituted;-   R⁴ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together with a oxygen atom an epoxy group or a    cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or heteroaryl;

R⁵ is in each instance independently selected from the group consistingof halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷, —NR⁸COR⁹,—NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR⁶, —SO₂NR⁶R⁷, —OOCR⁸, —CR⁸R⁹OH,R⁸OH, and -A or two substituents on adjacent carbon atoms together witha oxygen atom form an epoxy group or a cycloalkyl, cycloheteroalkyl,alicyclic system, aryl or heteroaryl, optionally substituted;

-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;-   A is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃,

C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particularC₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferablymethenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃,C₄, C₅, or C₆ alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, inparticular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly,decahydro-naphthalenyl; alkoxy, in particular C₁-C₆ alkoxy, e.g. C₁, C₂,C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy,iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;alkoxyalkyl, in particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl,ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g.C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl,decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl,decahydro-quinazolinyl; an alicyclic system, which may comprise one ormore heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the groupconsisting of O, S, or N; in particular 1,2-dihydropyridinyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, inparticular phenyl, naphthalenyl or anthracenyl; and heteroaryl, inparticular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

-   m is an integer from 0 to 8, i.e. 0, 1, 2, 3, 4, 5, 6, 7, or 8,    preferably 3;-   n is an integer from 0 to 6, i.e. 0, 1, 2, 3, 4, 5, or 6; preferably    1;-   X is O or S; preferably O;-   Y is O or NH or S; preferably O; and    the bicyclo[5.3.0]decyl moiety (formed of R¹ and R²) may contain    one, two or three double bonds, preferably one double bond and the    dashed bond is present or not, preferably the dashed bond is    present.

In a preferred method of the present invention the potential agonist orpotential antagonist structurally related to arglabin or arborsecin hasa structure according to formula (V)

wherein

-   R³ is H, OH, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in    particular C₁-C₆ alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    preferably C₁-C₆ alkyl, more preferably methyl; optionally    substituted;-   R⁴ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together with a oxygen atom an epoxy group;-   R⁵ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₂, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;-   A is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted;-   m is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4; preferably O;-   n is an integer from 0 to 3, i.e. 0, 1, 2, or 3,; preferably O;-   X is O or S; preferably O;-   Y is O or NH or S; preferably O; and    the bicycle[5.3.0]decyl may contain one, two further double bonds,    preferably one double bond and the dashed bond may be present or    not, preferably the dashed bond is present.

In a preferred method of the present invention the potential agonist orpotential antagonist structurally related to absinthin has a structureaccording to formula (VI)

wherein

-   R³ is H, OH, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in    particular C₁-C₆ alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    preferably C₁-C₆ alkyl, more preferably methyl; optionally    substituted;-   R⁴ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together with a oxygen atom an epoxy group or a    cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or heteroaryl,    optionally substituted;-   R¹⁰ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms together with a oxygen atom form an epoxy group or a    cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or heteroaryl,    optionally substituted;-   R¹¹ is H, OH, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    methenyl, ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in    particular C₁-C₆ alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    preferably C₁-C₆ alkyl, more preferably methyl; optionally    substituted;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;-   A is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₂, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted;-   m is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 1;-   o is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4; preferably 1;-   X and X¹ is in each instance selected from O or S; preferably is in    both instances 0;-   Y and Y¹ is in each instance selected from O or NH or S; preferably    is in both instances O; and    either of the bicycle[5.3.0]decyl moieties may contain one or two    double bonds, preferably one double bond.

In a preferred method of the present invention the potential agonist orpotential antagonist structurally related to noscapine has a structureaccording to formula (VII)

wherein

-   R³ is cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅,    C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,    cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    bicyclo[5.3.0]decyl, octahydro-pentalenyl, octahydro-indenyl,    decahydro-azulenyl, adamantly, or decahydro-naphthalenyl;    heterocycloalkyl, preferably C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₋₄-heterocycloalkyl, in    particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8    diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6    diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7    diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8    diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8    diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8    diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,    1-aza-7,11-dioxo-spiro[5,5]undecyl, 1,4-diazabicyclo[2.2.2]oct-2-yl,    tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,    tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl,    decahydro-isoquinolinyl, decahydro-quinoxalinyl, or    decahydro-quinazolinyl; an alicyclic system, preferably    C₃-C₁₄-alicyclic system, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-alicyclic system, in particular cyclopropenyl,    cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,    cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl,    spiro[3,4]octenyl, spiro[4,3]octenyl, spiro[3,5]nonenyl,    spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl,    spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl,    bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl,    bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl,    bicyclo[5.3.0]decenyl, hexahydro-pentalenyl, hexahydro-indenyl,    octahydro-azulenyl, or octahydro-naphthalenyl, or a derivative    thereof, wherein 1, 2 or 3 carbon atoms are replaced by a heteroatom    each independently selected from the group consisting of nitrogen,    sulphur, or oxygen; aryl, in particular phenyl, naphthalenyl or    anthracenyl; or heteroaryl, in particular furanyl, thienyl,    oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,    pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,    isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl,    pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; preferably decahydro-naphthalenyl, cyclodecyl,    octahydro-naphthalenyl, or cyclodecenyl; optionally substituted;-   R¹² is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together an alicyclic system, aryl or heteroaryl,    optionally substituted;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;

A is selected from the group consisting of alkyl, in particular C₁-C₆alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particularC₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl,spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy, inparticular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particularC₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g.C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl,decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl,decahydro-quinazolinyl; an alicyclic system, which may comprise one ormore heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the groupconsisting of O, S, or N; in particular 1,2-dihydropyridinyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, inparticular phenyl, naphthalenyl or anthracenyl; and heteroaryl, inparticular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

-   q is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 1;-   X is selected from O or S; preferably O;-   Y is selected from O or NH or S; preferably O.

In a preferred method of the present invention the potential agonist orpotential antagonist structurally related to noscapine has a structureaccording to formula (VIII)

wherein

-   R¹² is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together with a oxygen atom an epoxy group or a    cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or heteroaryl,    optionally substituted;-   R¹³ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together an alicyclic system, aryl or heteroaryl,    optionally substituted;-   R¹⁴ and R¹⁵ together form a cycloalkyl, preferably    C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,    C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,    cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,    spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl,    spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl,    bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,    bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, bicyclo[5.3.0]decyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, or decahydro-naphthalenyl; heterocycloalkyl, preferably    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₋₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, or decahydro-quinazolinyl; an alicyclic    system, preferably C₃-C₁₄-alicyclic system, e.g. C₃, C₄, C₅, C₆, C₇,    C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-alicyclic system, in particular    cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,    cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl,    spiro[3,3]heptenyl, spiro[3,4]octenyl, spiro[4,3]octenyl,    spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl,    spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl,    bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl,    bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl,    bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, bicyclo[5.3.0]decenyl,    hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or    octahydro-naphthalenyl, or a derivative thereof, wherein 1, 2 or 3    carbon atoms are replaced by a heteroatom each independently    selected from the group consisting of nitrogen, sulphur, or oxygen;    aryl, in particular phenyl, naphthalenyl or anthracenyl; or    heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;    preferably decahydro-naphthalenyl, cyclodecyl,    octahydro-naphthalenyl, or cyclodecenyl; optionally substituted;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;-   A is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted;-   q is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 1;-   r is an integer from 0 to 7, i.e. 0, 1, 2, 3, 4, 5, 6, or 7,    preferably 1-   X is selected from O or S; preferably O;-   Y is selected from O or NH or S; preferably O; and-   Z. is selected from O or NR′ or S; preferably NR′, wherein R′ is H    or alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆    alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,    iso-butyl, tert-butyl, pentyl, or hexyl.

In a further preferred embodiment of either method of the presentinvention the potential agonist or potential antagonist that is employedin the identification process is structurally related to amarogentin andhas a structure according to formula (IX)

wherein

-   R¹⁶ is H; OH; halogen, in particular F, Cl, Br or I; alkyl, in    particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl,    preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,    tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl,    e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkoxy, in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,    butoxy, iso-butoxy, tert-butoxy, pentoxy, hexoxy; alkoxyalkyl, in    particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    optionally substituted or is not present, if the dashed line is a    bond;-   R¹⁷ is in each instance independently selected from the group    consisting of H, OH, halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶,    —CONR⁶R⁷, —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E),    —SO₂NR⁶R⁷, —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A;-   R¹⁸ is H; OH; halogen, in particular F, Cl, Br or I; alkyl, in    particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl,    preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,    tert-butyl, pentyl, hexyl; alkenyl, in particular C₂-C₆ alkenyl,    e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkoxy, in particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,    butoxy, iso-butoxy, tert-butoxy, pentoxy, hexoxy; alkoxyalkyl, in    particular C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl,    ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,    propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl;    optionally substituted-   R¹⁹ sugar moiety, in particular mono or disaccharide, preferably    fructose, glucose, galactose, saccharose, ribose, desoxyribose, most    preferably glucose; optionally substituted;-   R²⁰ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together with a oxygen atom an epoxy group or a    cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or heteroaryl,    optionally substituted;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4, 5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;-   A is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl,    iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in    particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkenyl,    preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,    1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;    more preferably methyl; optionally substituted; and-   s is an integer from 0 to 3, i.e. 0, 1, 2, or 3, preferably 1.

In a more preferred embodiment the potential agonist or potentialantagonist structurally related to amarogentin and has a structureaccording to formula (X)

wherein R¹⁶, R¹⁷, R¹⁸, R²⁰, and s have the meanings and preferredmeanings outlined above and

-   R²¹ is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; preferably alkyl, in particular C₁-C₆ alkyl,    e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,    propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;    alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆    alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,    1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;    more preferably methenyl; optionally substituted 1, 2, 3, 4 or 5    times. In the most preferred embodiment R²¹ is phenyl, optionally    substituted.

In a further preferred embodiment of either method of the presentinvention the potential agonist or potential antagonist that is employedin the identification process is structurally related to humulon and hasa structure according to formula (XI)

wherein

-   R²² is H, OH, halogen, in particular F, Br, or Cl; alkyl, in    particular C₁-C₁₀ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, C₆ C₇, C₈, C₉ or    C₁₀ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,    iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₁₀    alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, C₆ C₇, C₈, C₉ or C₁₀ alkenyl,    preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,    1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;    3-methyl-but-2-enyl 4-methyl-pent-3-enyl; alkoxy, in particular    C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably    methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,    tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C₁-C₆    alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl,    methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,    ethoxypropyl, or propoxypropyl; preferably C₁-C₆ alkyl, more    preferably methyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.    C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    bicyclo[5.3.0]decyl, octahydro-pentalenyl, octahydro-indenyl,    decahydro-azulenyl, adamantly, or decahydro-naphthalenyl;    heterocycloalkyl, preferably C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in    particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8    diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6    diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7    diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8    diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8    diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8    diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,    1-aza-7,11-dioxo-spiro[5,5]undecyl, 1,4-diazabicyclo[2.2.2]oct-2-yl,    tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,    tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl,    decahydro-isoquinolinyl, decahydro-quinoxalinyl, or    decahydro-quinazolinyl; an alicyclic system, preferably    C₃-C₁₄-alicyclic system, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-alicyclic system, in particular cyclopropenyl,    cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,    cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl,    spiro[3,4]octenyl, spiro[4,3]octenyl, spiro[3,5]nonenyl,    spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl,    spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl,    bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl,    bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl,    bicyclo[5.3.0]decenyl, hexahydro-pentalenyl, hexahydro-indenyl,    octahydro-azulenyl, or octahydro-naphthalenyl, or a derivative    thereof, wherein 1, 2 or 3 carbon atoms are replaced by a heteroatom    each independently selected from the group consisting of nitrogen,    sulphur, or oxygen; aryl, in particular phenyl, naphthalenyl or    anthracenyl; or heteroaryl, in particular furanyl, thienyl,    oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,    pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,    isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl,    pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; preferably decahydro-naphthalenyl, cyclodecyl,    octahydro-naphthalenyl, or cyclodecenyl; optionally substituted;-   R²³ is H, OH, halogen, in particular F, Br, or Cl; alkyl, in    particular C₁-C₁₀ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, C₆ C₇, C₈, C₉ or    C₁₀ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,    iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₁₀    alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, C₆ C₇, C₈, C₉ or C₁₀ alkenyl,    preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,    1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;    3-methyl-but-2-enyl 4-methyl-pent-3-enyl; optionally substituted,    preferably with an oxo-group;-   R²⁴ is H, OH, halogen, in particular F, Br, or Cl; alkyl, in    particular C₁-C₁₀ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, C₆ C₇, C₈, C₉ or    C₁₀ alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,    iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C₁-C₁₀    alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, C₆ C₇, C₈, C₉ or C₁₀ alkenyl,    preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,    1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;    3-methyl-but-2-enyl 4-methyl-pent-3-enyl; alkoxy, in particular    C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably    methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,    tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C₁-C₆    alkoxy-C₁-C₆ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl,    methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,    ethoxypropyl, or propoxypropyl; preferably C₁-C₆ alkyl, more    preferably methyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g.    C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    bicyclo[5.3.0]decyl, octahydro-pentalenyl, octahydro-indenyl,    decahydro-azulenyl, adamantly, or decahydro-naphthalenyl;    heterocycloalkyl, preferably C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in    particular piperidinyl, morpholinyl, 1,3-diazacyclohexane, 1,8    diaza-spiro-[4,5]decyl, 1,7 diaza-spiro-[4,5]decyl, 1,6    diaza-spiro-[4,5]decyl, 2,8 diaza-spiro[4,5]decyl, 2,7    diaza-spiro[4,5]decyl, 2,6 diaza-spiro[4,5]decyl, 1,8    diaza-spiro-[5,4]decyl, 1,7 diaza-spiro-[5,4]decyl, 2,8    diaza-spiro-[5,4]decyl, 2,7 diaza-spiro[5,4]decyl, 3,8    diaza-spiro[5,4]decyl, 3,7 diaza-spiro[5,4]decyl,    1-aza-7,11-dioxo-spiro[5,5]undecyl, 1,4-diazabicyclo[2.2.2]oct-2-yl,    tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,    tetrahydrothien-3-yl, piperazinyl, decahydroquinolinyl,    decahydro-isoquinolinyl, decahydro-quinoxalinyl, or    decahydro-quinazolinyl; an alicyclic system, preferably    C₃-C₁₄-alicyclic system, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-alicyclic system, in particular cyclopropenyl,    cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,    cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl,    spiro[3,4]octenyl, spiro[4,3]octenyl, spiro[3,5]nonenyl,    spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl,    spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl,    bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl,    bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl,    bicyclo[5.3.0]decenyl, hexahydro-pentalenyl, hexahydro-indenyl,    octahydro-azulenyl, or octahydro-naphthalenyl, or a derivative    thereof, wherein 1, 2 or 3 carbon atoms are replaced by a heteroatom    each independently selected from the group consisting of nitrogen,    sulphur, or oxygen; aryl, in particular phenyl, naphthalenyl or    anthracenyl; or heteroaryl, in particular furanyl, thienyl,    oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,    pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl,    isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl,    pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; preferably decahydro-naphthalenyl, cyclodecyl,    octahydro-naphthalenyl, or cyclodecenyl; optionally substituted;-   R²⁵ is in each instance independently selected from the group    consisting of halogen, —NO₂, —CN, —OR⁶, —NR⁶R⁷, —COOR⁶, —CONR⁶R⁷,    —NR⁸COR⁹, —NR⁸COR⁹, —NR⁸CONR⁶R⁷, —NR⁹SO₂A, —COR^(E), —SO₂NR⁶R⁷,    —OOCR⁸, —CR⁸R⁹OH, R⁸OH, and -A or two substituents on adjacent    carbon atoms form together with a oxygen atom an epoxy group or a    cycloalkyl, cycloheteroalkyl, alicyclic system, aryl or heteroaryl,    optionally substituted;-   R⁶ and R⁷ is each independently selected from the group consisting    of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆    alkynyl; cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted;-   R⁸ and R⁹ is each independently selected from the group consisting    of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄,    C₅, or C₆ alkyl, preferably methyl, ethyl, propyl, iso-propyl,    butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular    C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl, preferably    ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl,    1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C₂-C₆    alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in    particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR⁶R⁷;

A is selected from the group consisting of alkyl, in particular C₁-C₆alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl,propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆alkenyl, preferably methenyl, ethenyl, 1-propenyl, 2-propenyl,1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particularC₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₂, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl,spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl,spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl,bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl,decahydro-azulenyl, adamantly, decahydro-naphthalenyl; alkoxy, inparticular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particularC₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g.C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl, piperazinyl,decahydroquinolinyl, decahydro-isoquinolinyl, decahydro-quinoxalinyl,decahydro-quinazolinyl; an alicyclic system, which may comprise one ormore heteroatoms, e.g. 1, 2, 3, or 4, preferably selected from the groupconsisting of O, S, or N; in particular 1,2-dihydropyridinyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridyl,1,2-dihydropyrazyl, 1,2,3,4-tetrahydropyrazyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, inparticular phenyl, naphthalenyl or anthracenyl; and heteroaryl, inparticular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;

-   t is an integer from 0 to 5, i.e. 0, 1, 2, 3, 4 or 5, preferably 1;    and-   X is selected from O or S; preferably O.

In a further preferred embodiment of either method of the presentinvention the potential agonist or potential antagonist is structurallyrelated to humulon and has a structure according to formula (XII)

wherein

-   R²², R²⁴ and R²⁵ have their above indicated meaning and preferred    meanings and-   t is an integer from 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 1;    and-   X is selected from O or S; preferably O.

In a further preferred embodiment of either method of the presentinvention the potential agonist or potential antagonist is structurallyrelated to N,N′-diethylurea and has a structure according to formula(XIII)

wherein

-   R²⁶ is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄,    C₅, or C₆ alkynyl; cycloalkyl, e.g. C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl,    2-methylene-decahydro-naphthalenyl, or    2-methylene-decahydro-naphthalen-1-yl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular C₁-C₆ alkoxy-C₁-C₆    alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl,    methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,    ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexanyl, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, or decahydro-quinazolinyl; an alicyclic    system, which may comprise one or more heteroatoms preferably    selected from the group consisting of O, S, or N; in particular    1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; or heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted;-   R²⁷ is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, in particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄,    C₅, or C₆ alkynyl; cycloalkyl, e.g. C₃-C₁₄-cycloalkyl, e.g. C₃, C₄,    C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in    particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl,    2-methylene-decahydro-naphthalenyl, or    2-methylene-decahydro-naphthalen-1-yl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular C₁-C₆ alkoxy-C₁-C₆    alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl,    methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,    ethoxypropyl, or propoxypropyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexanyl, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, or decahydro-quinazolinyl; an alicyclic    system, which may comprise one or more heteroatoms preferably    selected from the group consisting of O, S, or N; in particular    1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; or heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted    or-   R²⁶ and R²⁷ together form a heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular, imidazolidinyl,    1,3-diazacyclohexanyl, 1,3-diazacycloheptanyl, or    decahydro-quinazolinyl; an alicyclic system comprising two nitrogen    atoms indicated in formula (I) and which may comprise one or more    further heteroatoms preferably selected from the group consisting of    O, S, or N; in particular dihydro-imidazolyl, e.g.    1,2-dihydro-imidazolyl, dihydro-pyrimidinyl, e.g. 4,5,    dihydro-pyrimidinyl, 1,2-dihydropyrimidinyl,    2,3-dihydro-1H-benzoimidazolyl,    2,3-dihydro-1H-imidazo[4,5-c]pyridinyl,    2,3-dihydro-1H-imidazo[4,5-d]pyridinyl, or    6,7-dihydro-5H-imidazo[4,5-c]pyridazinyl; or heteroaryl, in    particular imidazolyl, 1,2,4-triazolyl, pyrimidinyl,    1,2,4-triazinyl, 1,3,5-triazinyl, benzimidazolyl, quinazolinyl,    1,2,4-benzotriazinyl, 3H-imidazo[4,5-b]pyridinyl,    3H-imidazo[4,5-c]pyridinyl, 1H-imidazo[4,5-b]pyrazinyl, 7H-purine,    or 7H-Imidazo[4,5-c]pyridazinyl; optionally substituted.

In a further preferred embodiment of either method of the presentinvention the potential agonist or potential antagonist structurallyrelated to azathioprine, azepinon, benzoin, brucine, camphor,cascarillin, chlorhexidine, herbolid A, papaverin, picrotoxinin, or(−)-a-thujon are based on the known structure of this compounds (seeFIG. 1) and are derived by introducing and/or exchanging one or more,preferably two, three or four substituents. Preferably, the introductionor exchange of one or two substituents in each instance independentlyselected from the group consisting of halogen, in particular F, Cl, Bror I; —NO₂; —CN; —OR^(c); —NR^(c)R^(d); —COOR^(c); —CONR^(c)R^(d);—NR^(a)COR^(b); —NR^(a)COR^(b); —NR^(a)CONR^(c)R^(d); —NR^(b)SO₂D;—COR^(c), —SO₂NR^(c)R^(d); —OOCR^(a); —CR^(a)R^(b)OH; R^(a)OH; and -D;

-   R^(a) and R^(b) is each independently selected from the group    consisting of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁,    C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl,    iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in    particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl,    preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in    particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl;    cycloalkyl, in particular C₃-C₁₋₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆,    C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,    cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g. C₃-C₁₄—    heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,    C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,    1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    -NR^(e)R^(e);-   R^(c) and R^(d) is each independently selected from the group    consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁,    C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl,    iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in    particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl,    preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂,    C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particular    C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,    C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,    cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,    spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl,    spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl,    bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,    bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl,    octahydro-indenyl, decahydro-azulenyl, adamantly,    decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted; and-   D is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₂, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted.

The potential agonists or potential antagonists, which are employed inthe methods of the present invention can be synthesized by methods andstandard procedures known to those skilled in the art, i.e. as describedin the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), under reaction conditionswhich are known to those skilled in the art and suitable for the saidreactions.

The selected, e.g. isolated, antagonist or agonist is in a preferredembodiment chemical modified in a further step. Again this chemicalmodification can be effected by a variety of methods known in the art,which include without limitation the introduction of one or more,preferably two, three or four substituents or the exchange of one ormore substituents. Preferably, the introduction or exchange of one ortwo substituents in each instance independently selected from the groupconsisting of halogen, in particular F, Cl, Br or I; NO₂; —CN; —OR^(c),—NR^(c)R^(d); —COOR^(c); —CONR^(c)R^(d); —NR^(a)COR^(b); —NR^(a)COR^(b);—NR^(a)CONR^(c)R^(d); —NR^(b)SO₂D; —COR^(c)—SO₂NR^(c)R^(d); —OOCR^(a);—CR^(a)R^(b)OH; R^(a)OH; and -D;

-   R^(a) and R^(b) is each independently selected from the group    consisting of hydrogen; alkyl, in particular C₁-C₆ alkyl, e.g. C₁,    C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl,    iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in    particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl,    preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in    particular C₂-C₆ alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl;    cycloalkyl, in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆,    C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,    cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl,    spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl,    spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; heterocycloalkyl, e.g. C₃-C₁₄—    heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,    C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl, morpholinyl,    1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydro-quinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; alkoxy, in    particular C₁-C₆ alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy,    preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,    iso-butoxy, tert-butoxy, pentoxy, or hexoxy; aryl, in particular    phenyl, naphthalenyl or anthracenyl; aralkyl; preferably C₁-C₆    aralkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; heteroaryl, in    particular furanyl, thienyl, oxazolyl, isoxazolyl,    1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,    pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,    1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,    pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,    1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,    2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,    indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,    1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl,    quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,    quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; and    —NR^(c)R^(c);-   R^(c) and R^(d) is each independently selected from the group    consisting of hydrogen, alkyl, in particular C₁-C₆ alkyl, e.g. C₁,    C₂, C₃, C₄, C₅, or C₆ alkyl, preferably methyl, ethyl, propyl,    iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in    particular C₂-C₆ alkenyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkenyl,    preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl,    2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, e.g. C₂,    C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl, in particular    C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₂, C₈, C₉, C₁₀, C₁₁, C₁₂,    C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,    cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,    spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl,    spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl,    bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,    bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl,    octahydro-indenyl, decahydro-azulenyl, adamantly,    decahydro-naphthalenyl; heterocycloalkyl, e.g.    C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,    C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; and aralkyl, preferably C₁-C₆ aralkyl, e.g.    C₁, C₂, C₃, C₄, C₅, or C₆ aralkyl; or together form a heteroaryl, in    particular, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,    indoxazinyl, 2,1-benzisoxazolyl, 1,2-benzisothiazolyl,    2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,    2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl,    or 1,2,4-benzotriazinyl; optionally substituted; and-   D is selected from the group consisting of alkyl, in particular    C₁-C₆ alkyl, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, preferably    methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,    pentyl, hexyl; alkenyl, in particular C₁-C₆ alkenyl, e.g. C₁, C₂,    C₃, C₄, C₅, or C₆ alkenyl, preferably methenyl, ethenyl, 1-propenyl,    2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,    3-butenyl; alkynyl, e.g. C₂, C₃, C₄, C₅, or C₆ alkynyl; cycloalkyl,    in particular C₃-C₁₄-cycloalkyl, e.g. C₃, C₄, C₅, C₆, C₂, C₈, C₉,    C₁₀, C₁₁, C₁₂, C₁₃ or C₁₄-cycloalkyl, in particular cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl,    spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl,    spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,    bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl,    octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl,    adamantly, decahydro-naphthalenyl; alkoxy, in particular C₁-C₆    alkoxy, e.g. C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, preferably methoxy,    ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,    pentoxy, or hexoxy; alkoxyalkyl, in particular    C₁-C₆-alkoxy-C₁-C₆-alkyl, e.g. methoxymethyl, ethoxymethyl,    propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,    methoxypropyl, ethoxypropyl, or propoxypropyl; heterocycloalkyl,    e.g. C₃-C₁₄-heterocycloalkyl, e.g. C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,    C₁₁, C₁₂, C₁₃ or C₁₄-heterocycloalkyl, in particular piperidinyl,    morpholinyl, 1,3-diazacyclohexane, 1,8 diaza-spiro-[4,5]decyl, 1,7    diaza-spiro-[4,5]decyl, 1,6 diaza-spiro-[4,5]decyl, 2,8    diaza-spiro[4,5]decyl, 2,7 diaza-spiro[4,5]decyl, 2,6    diaza-spiro[4,5]decyl, 1,8 diaza-spiro-[5,4]decyl, 1,7    diaza-spiro-[5,4]decyl, 2,8 diaza-spiro-[5,4]decyl, 2,7    diaza-spiro[5,4]decyl, 3,8 diaza-spiro[5,4]decyl, 3,7    diaza-spiro[5,4]decyl, 1-aza-7,11-dioxo-spiro[5,5]undecyl,    1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,    tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl,    piperazinyl, decahydroquinolinyl, decahydro-isoquinolinyl,    decahydro-quinoxalinyl, decahydro-quinazolinyl; an alicyclic system,    which may comprise one or more heteroatoms, e.g. 1, 2, 3, or 4,    preferably selected from the group consisting of O, S, or N; in    particular 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyridyl, 1,2-dihydropyrazyl,    1,2,3,4-tetrahydropyrazyl, cyclopropenyl, cyclobutenyl,    cyclopentenyl, cyclohexenyl, cycloheptenyl; aryl, in particular    phenyl, naphthalenyl or anthracenyl; and heteroaryl, in particular    furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl,    1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,    thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,    pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,    1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,    isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl,    benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl,    benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,    benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl,    quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or    1,2,4-benzotriazinyl; optionally substituted.

The thus modified antagonist is then tested with the first embodiment ofthe method of the present invention. The modified antagonist iscontacted with the hTAS2R¹⁴, hTAS2R¹⁰ or hTAS2R⁴ polypeptide as such orwith the polypeptide expressed in a host cell, which has been contactedprior, concomitantly or after step (1) with absinthin, artemorin,amarogentin, arglabin, azathioprine, azepinon, benzoin, brucine,camphor, cascarillin, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, papaverin, parthenolid, picrotoxinin, arborescinor (−)-a-thujon or an agonistic compound structurally related toabsinthin, artemorin, amarogentin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin or (−)-a-thujon and subsequentlyinhibition of the bitter taste receptor activity by the modifiedantagonist is measured. The activation and, thus, also the inhibition ofactivation of the hTAS2R14, hTAS2R10 or hTAS2R4 protein can be measured,e.g. by the intracellular calcium release mediated. If needed the stepsof selecting the antagonist, modifying the compound, contacting theantagonist with a polypeptide or a host cell and measuring of theactivation of the bitter taste receptor activity can be repeated afurther or any given number of times as required. The above describedmethod is also termed “directed evolution” of an antagonist since itinvolves a multitude of steps including modification and selection,whereby antagonizing compounds are selected in an “evolutionary” processoptimizing their capabilities with respect to a particular property,e.g. their ability to inhibit or modulate the activity of hTAS2R14,hTAS2R10 or hTAS2R4, in particular inhibit or stimulate theintracellular release of calcium. Preferably, a modified antagonist isselected that reduces the activity of hTAS2R14, hTAS2R10 or hTAS2R4stimulated by absinthin, artemorin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, chlorhexidine, N,N′-diethylthiourea, herbolidA, isohumulone, noscapine, parthenolid, or arborsecin for hTAS2R14;absinthin, artemorin, amarogentin, arglabin, azathioprine, benzoin,camphor, cascarillin, papaverin, parthenolid, picrotoxinin, arborescinor (−)-a-thujon for hTAS2R10; or artemorin, amarogentin, azathioprine orcampor for hTAS2R4 at least as good as the identified antagonist used asbasis for the modified antagonist at the same molar concentration. Morepreferably, the modified antagonist shows a stronger reduction at thesame molar concentration, preferably at least a 10% stronger reduction,20%, 30%, 40%, 50%, 60, or 70% stronger reduction.

The above stated process of directed evolution also can be applied tooptimize the capability of an isolated agonist. This method comprisesthe modification of the identified agonist as indicated above andtesting the activating activity of this modified agonist in a methodaccording to the second aspect of this invention. Optionally, furtherrounds of chemical modification are carried out. Preferably, a modifiedagonist is selected that increases the activity of hTAS2R14, hTAS2R10 orhTAS2R4 at least as good as the identified agonist at the same molarconcentration. More preferably, the modified antagonist shows a strongeractivation at the same molar concentration, preferably at least a 10%stronger activation, 20%, 30%, 40%, 50%, 60, 70%, 100%, 200%, 1000%stronger activation.

In a preferred embodiment, compounds structurally related to absinthin,artemorin, amarogentin, arglabin, azathioprine, azepinon, benzoin,brucine, camphor, cascarillin, chlorhexidine, N,N′-diethylthiourea,herbolid A, isohumulone, noscapine, papaverin, parthenolid,picrotoxinin, arborescin or (−)-a-thujon are used in the first round ofabove stated directed evolution methods.

The term “structurally related agonist” refers to agonists, which arederived from absinthin, artemorin, amarogentin, arglabin, azathioprine,azepinon, benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin and (−)-a-thujon, respectively, bychemical modification and which elicit at least 20% (e.g., at least:20%; 30%; 40%; 50%; 60%; 70%; 80%; 90%; 95%; 98%; 99%; 99.5%; or 100%,150%, 200%, 300%, 500%, 1,000%, 10,000% or more) of the bitter tastereceptor activity, if compared to the respective unmodified agonist atthe same molar concentration. Preferably, the assay system used is thecellular assay system described in more detail in the Examples.Preferred structurally related agonists have a structure as describedabove under formulas (I) to (XIII).

The term “structurally related antagonist” of absinthin, artemorin,amarogentin, arglabin, azathioprine, azepinon, benzoin, brucine,camphor, cascarillin, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, papaverin, parthenolid, picrotoxinin, arborescinand (−)-a-thujon, respectively, is a substance, which is derived fromabsinthin, artemorin, amarogentin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin and (−)-a-thujon by chemicalmodification and which lowers the hTAS2R14, hTAS2R10 and hTAS2R4 bittertaste receptor activity, respectively, determined in the presence ofabsinthin, artemorin, amarogentin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin and (−)-a-thujon, respectively, byat least 10% (e.g. at least 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 95%, 98%, 99%, 99,5% or 100%) Preferably, the antagonisticderivative exerts this action, when it is contacted prior, concomitantlyor after, preferably concomitantly, to the contacting of the hTAS2R14,hTAS2R10 and hTAS2R4 polypeptide, respectively, the host cell expressingthe hTAS2R14, hTAS2R10 and hTAS2R4 polypeptide, respectively, or thevector comprising the hTAS2R14, hTAS2R10 and hTAS2R4 polypeptide,respectively, with the agonist. Preferred structurally relatedantagonists have a structure as described above under formulas (I) to(XIII).

In order to express cDNAs encoding the receptors, one typicallysubclones receptor cDNA into an expression vector that contains a strongpromoter to direct transcription, a transcription/translationterminator, and a ribosome-binding site for translational initiation.Suitable bacterial promoters are well known in the art, e.g., E. coli,Bacillus sp., and Salmonella, and kits for such expression systems arecommercially available. Similarly eukaryotic expression systems formammalian cells, yeast, and insect cells are well known in the art andare also commercially available. The eukaryotic expression vector maybe, for example an adenoviral vector, an adeno-associated vector, or aretroviral vector.

In addition to the promoter, the expression vector typically contains atranscription unit or expression cassette that contains all theadditional elements required for the expression of the receptor-encodingnucleic acid in host cells. A typical expression cassette thus containsa promoter operatively linked to the nucleic acid sequence encoding thereceptor and signals required for efficient polyadenylation of thetranscript, ribosome binding sites, and translation termination. Thenucleic acid sequence encoding the receptor may typically be linked to amembrane-targeting signal such as the N-terminal 45 amino acids of therat somatostatin receptor 3 sequence to promote efficient cell-surfaceexpression of the recombinant receptor. Additional elements of thecassette may include, for example enhancers.

An expression cassette should also contain a transcription terminationregion downstream of the structural gene to provide for efficienttermination. The termination region may be obtained from the same geneas the promoter sequence or may be obtained from different genes.

The particular expression vector used to transport the geneticinformation into the cell is not particularly critical. Any of theconventional vectors used for expression in eukaryotic or prokaryoticcells may be used. Standard bacterial expression vectors includeplasmids such as pBR322 based plasmids, pSKF, pET23D, and fusionexpression systems such as GST and LacZ, but there are many more knownin the art to the skilled person that can be usefully employed.

Expression vectors containing regulatory elements from eukaryoticviruses are typically used in eukaryotic expression vectors, e.g. SV40vectors, papilloma virus vectors, and vectors derived from Epstein-Barrvirus. Other exemplary eukaryotic vectors include pMSG, pAV009/A.sup. +,pMT010/A.sup.+, pMAMneo-5, baculovirus pDSVE, pcDNA3.1, pIRES and anyother vector allowing expression of proteins under the direction of theSV40 early promoter, SV40 late promoter, metallothionein promoter,murine mammary tumor virus promoter, Rous sarcoma virus promoter,polyhedrin promoter, or other promoters shown effective for expressionin eukaryotic cells.

Some expression systems have markers that provide gene amplificationsuch as thymidine kinase, hygromycin B phosphotransferase, anddihydrofolate reductase. Alternatively, high yield expression systemsnot involving gene amplification are also suitable.

The elements that are typically included in expression vectors alsoinclude a replicon that functions in E. coli, a gene encoding drugresistance to permit selection of bacteria that harbor recombinantplasmids, and unique restriction sites in nonessential regions of theplasmid to allow insertion of eukaryotic sequences. The particular drugresistance gene chosen is not critical, any of the many drug resistancegenes known in the art are suitable. The prokaryotic sequences areoptionally chosen such that they do not interfere with the replicationof the DNA in eukaryotic cells, if necessary.

Standard transfection methods can be used to produce bacterial,mammalian, yeast or insect cell lines that express large quantities ofthe receptor, which are then purified using standard techniques. Any ofthe well-known procedures for introducing foreign polynucleotidesequences into host cells may be used. These include the use of calciumphosphate transfection, polybrene, protoplast fusion, electroporation,liposomes, microinjection, plasma vectors, viral vectors and any of theother well known methods for introducing cloned genomic DNA, cDNA,synthetic DNA or other foreign genetic material into a host cell. It isonly necessary that the particular genetic engineering procedure used becapable of successfully introducing at least one gene into the host cellcapable of expressing the receptor.

After the expression vector is introduced into the cells, thetransfected cells may be cultured under conditions favouring expressionof the receptor, which is recovered from the culture using standardtechniques. For example the cells may be burst open either mechanicallyor by osmotic shock before being subject to precipitation andchromatography steps, the nature and sequence of which will depend onthe particular recombinant material to be recovered. Alternatively, therecombinant protein may be recovered from the culture medium in whichthe recombinant cells had been cultured.

The activity of the receptor described herein can be assessed using avariety of in vitro and in vivo assays to determine functional,chemical, and physical effects, e.g., measuring ligand binding,secondary messengers (e.g., cAMP, cGMP, IP₃, DAG, or Ca²⁺) ion flux,phosphorylation levels, transcription levels, of reporter constructsneurotransmitter levels, and the like. Such assays are used in themethod of the present invention to test for the activity of thereceptors.

Samples or assays that are treated with a potential receptor agonist orantagonist may be compared to control samples which are untreated(agonist control) or which are untreated or have been treated with anagonist (antagonist control), to examine the extent of modulation.Control samples are assigned a relative receptor activity value of 100.Inhibition of receptor activity is achieved when the receptor activityvalue relative to the control is lower, and conversely receptor activityis enhanced when activity relative to the control is higher in thepresence of identical amounts of the respective agonist or antagonist,respectively.

The effects of the test compounds upon the function of the receptors canbe measured by examining any of the parameters described above. Anysuitable physiological change that affects receptor activity can be usedto assess the influence of a test compound on the receptors usable inthe methods of this invention. When the functional consequences aredetermined using intact cells or animals, these consequences canmeasured by any means known to those skilled in the art, e.g., patchclamping, voltage-sensitive dyes, whole cell currents, radioisotopeefflux, inducible markers, oocyte bitter taste receptor gene expression;tissue culture cell bitter taste receptor expression; transcriptionalactivation of bitter taste receptor genes; ligand binding assays;voltage, membrane potential and conductance changes; ion, preferablysodium or calcium ion flux assays, for example measuring calcium levelsusing calcium sensitive dyes such as Fluo-3, Fluo-4 or Fura-2; changesin intracellular second messengers such as cAMP, cGMP, and inositoltriphosphate (IP₃); changes in intracellular calcium levels;neurotransmitter release, and the like. These assays may be performed onintact cells expressing a bitter taste receptor polypeptide, onpermeabilized cells, or on membrane fractions produced by standardmethods.

Preferred assays for G-protein coupled receptors include cells that areloaded with ion sensitive dyes to report receptor activity. In assaysfor identifying modulatory compounds, changes in the level of ions inthe cytoplasm or membrane voltage will be monitored using an ionsensitive or membrane voltage fluorescent indicator, respectively. ForG-protein coupled receptors, promiscuous G-proteins such as Gα15 andGαi6 and chimeric G-proteins can be used in the assay of choice (see,for example, Wilkie et al. (1991) Proc. Nat. Acad. Sci. USA 88:10049-10053). Such promiscuous G-proteins allow coupling of a wide rangeof receptors to G-protein dependent signal pathways.

Receptor activation typically initiates subsequent intracellular events,e.g. increases in second messengers such as IP₃, which releasesintracellular stores of calcium ions. Activation of some G-proteincoupled receptors stimulates the formation of inositol trisphosphatethrough phospholipase C-mediated hydrolysis of phosphatidylinositolbisphosphate (Berridge & Irvine (1984) Nature 312: 315-21). IP₃ in turnstimulates the release of intracellular calcium ion stores. Thus, achange in cytoplasmic calcium ion levels, or a change in secondmessenger levels such as IP₃ can be used to assess G-protein coupledreceptor function. Cells expressing such G-protein coupled receptors mayexhibit increased cytoplasmic calcium levels as a result of contributionfrom both intracellular stores and via activation of ion channels, inwhich case it may be desirable, although not necessary, to conduct suchassays in calcium-free buffer, optionally supplemented with a chelatingagent such as EGTA, to distinguish fluorescence response resulting fromcalcium release from internal stores.

In a preferred embodiment, receptor activity is measured by expressingthe hTAS2R14, hTAS2R10 or hTAS2R4 bitter taste receptors in aheterologous cell with a G-protein, such as Gα15, Gα16, transducin,gustducin, or a chimeric G-protein that links the receptor to aphospholipase C signal transduction pathway. In another aspect of theinvention, only the extracellular domain of the respective bitter tastereceptor is expressed as a chimeric transmembrane fusion protein. Apreferred cell line is HEK-293, although other mammalian cell lines arealso preferred such as CHO and COS cells. Modulation of tastetransduction is assayed by measuring changes in intracellular Ca²⁺levels, which change in response to modulation of the receptor signaltransduction pathway via administration of a molecule that associateswith the receptor. Changes in Ca²⁺ levels are optionally measured usingfluorescent Ca²⁺ indicator dyes and fluorometric imaging. The activityof the signalling molecule and the increase or decrease of that activityin response to the potential agonist or antagonist can be determined asoutlined above with respect to the identification of bitter tastereceptor taste activity. The respectively indicated percent increases ordecreases of the activity, which are required to qualify as antagonistor agonist do apply mutatis mutandis. Additionally the term “contacting”has the meaning as outlined above. Preferably the signalling moleculeand/or the promiscuous G-protein has been introduced into the cell. Thetypes of cell lines, which are preferred are those indicated above.

In yet another embodiment, the ligand-binding domains of the receptorscan be employed in vitro in soluble or solid-state reactions to assayfor ligand binding. Ligand binding to a bitter taste receptor, or adomain of a bitter taste receptor, such as e.g. the extracellulardomain, can be tested in solution, in a bilayer membrane attached to asolid phase, in a lipid monolayer or vesicles. Thereby, the binding of amodulator to the receptor, or domain, can be observed using changes inspectroscopic characteristics, e.g. fluorescence, fluorescencepolarization, plasmon resonance, absorbance or refractive index; orhydrodynamic (e.g. shape), chromatographic, or solubility properties, asis generally known in the art.

The compounds tested as modulators, i.e. potential agonists andantagonists, of the receptors can be any small chemical compound, or abiological entity, such as a protein, sugar, nucleic acid or lipid.Typically, test compounds will be small chemical molecules. Essentiallyany chemical compound can be used as a potential modulator or ligand inthe assays of the invention, although knowledge of the ligandspecificity of an individual receptor would enable the skilled person tomake an intelligent selection of interesting compounds. The assays maybe designed to screen large chemical libraries by automating the assaysteps and providing compounds from any convenient source to assays,which are typically run in parallel (e.g., in microtiter formats onmicrotiter plates in robotic assays). The skilled person will understandthat there are many suppliers of libraries of chemical compounds.

Assays may be run in high throughput screening methods that involveproviding a combinatorial chemical or peptide library containing a largenumber of potential therapeutic, or tastant compounds (that arepotential ligand compounds). Such libraries are then screened in one ormore assays, as described herein, to identify those library members(particular chemical species or subclasses) that display a desiredcharacteristic activity. The compounds thus identified can serve as leadcompounds to further develop modulators for final products, or canthemselves be used as actual modulators. A combinatorial chemicallibrary is a collection of diverse chemical compounds generated byeither chemical synthesis or biological synthesis, by combining a numberof chemical “building blocks” such as reagents. For example, a linearcombinatorial chemical library such as a polypeptide library is formedby combining a set of chemical building blocks (amino acids) in everypossible way for a given compound length (i.e., the number of aminoacids in a polypeptide compound). Millions of chemical compounds can besynthesized through such combinatorial mixing of chemical buildingblocks.

Preparation and screening of combinatorial chemical libraries is wellknown to those of skill in the art and no more needs to be stated here.

In the high throughput assays of the invention, it is possible to screenup to several thousand different modulators or ligands in a single day.In particular, each well of a microtiter plate can be used to run aseparate assay against a selected potential modulator, or, ifconcentration or incubation time effects are to be observed, every 5-10wells can test a single modulator. Thus, a single standard microtiterplate can assay about 100 (e.g., 96) modulators. If 1536 well plates areused, then a single plate can easily assay from about 100 to about 1500different compounds. It is possible to assay several different platesper day; assay screens for up to about 6,000-20,000 different compoundsis possible using the integrated systems of the invention.

Antagonists identified by method described herein above, or developmentcompounds formed from such antagonists can be administered directly to ahuman subject to modulate, e.g. inhibit, bitter taste. Alternatively,such compounds can be formulated with other ingredients of preparationsto be taken orally, for example, foods, including animal food, andbeverages, pharmaceutical or nutraceutical or homeopathic preparations.

Therefore, another aspect of the invention is a method for theproduction of food, a food precursor material or additive employed inthe production of foodstuff comprising the step of admixing one or moreof the above described isolated agonists, isolated antagonist, modifiedagonists, modified antagonists of hTAS2R14, hTAS2R10 and hTAS2R4 bittertaste receptor activity, respectively, with foodstuff or food precursormaterial or additive employed in the production of foodstuff.

Bitter taste is a particular problem when orally administeringpharmaceuticals, which often have an unpleasant bitter taste. Inparticular in elderly persons, children and chronically ill patientsthis taste can lead to a lack of compliance with a treatment regimen. Inaddition in veterinary applications the oral administration of bittertasting pharmaceuticals can be problematic. Therefore, a further aspectof the invention is a method for the production of a nutraceutical orpharmaceutical composition comprising the step of admixing the isolatedantagonist or the modified antagonists of hTAS2R14, hTAS2R10 or hTAS2R4bitter taste receptor activity with an active agent and optionally witha pharmaceutically acceptable carrier and/or adjuvants, in apharmaceutically acceptable form.

Bitter tasting substances such as agonists of bitter taste receptorsdescribed herein are also useful supplements to serve as a safetyadditive in household (for example dissolvers, soaps, householdchemicals) automotive and garden products. To prevent e.g. ingestion ofsuch toxic substances, the amount of antagonist formulated with suchproducts must be sufficient to effect an repellent response in the humanor animal subject. Bitter tasting substances such as agonists of bittertaste receptors are also utilized to prevent nail-chewing and serve asrepellent for animals including fish.

Therefore, another aspect of the invention is a method for theproduction of an animal repellent, precursor material or additiveemployed in the production of an animal repellent comprising the stepsof admixing the isolated agonists, isolated antagonist, modifiedagonists or modified antagonists of hTAS2R14, hTAS2R10 and hTAS2R4bitter taste receptor activity, respectively, as an active ingredientwith an animal repellent or a precursor material or additive employed inthe production of an animal repellent.

Consequently, a further aspect of the invention is an animal repellent,precursor material or additive employed in the production of an animalrepellent producible as stated above.

A further aspect of the invention is food stuff, food precursor materialor additive employed in the production of foodstuff producible accordingto the method of the invention.

Also comprised is a nutraceutical or pharmaceutical compositionproducible according to the method of the invention, comprising at leastone nutraceutically or pharmaceutically active agent, an optionalpharmaceutically acceptable carrier and/or adjuvants. Thesepharmaceutical and nutraceutical compositions comprise both products forhuman and animal consumption.

The amount of compound including an agonist or antagonist of presentinvention to be taken orally must be sufficient to effect a beneficialresponse in the subject, preferably human subject, and will bedetermined by the efficacy of the particular taste modulators and theexistence, nature, and extent of any adverse side-effects that accompanythe administration of a particular compound.

A further aspect of the present invention is the use of an agonist ofhTAS2R14, hTAS2R10 or hTAS2R4 bitter taste receptor activity isolatedaccording to the method of the invention to enhance bitter taste.

Also comprised is the use of an agonist of bitter taste receptoractivity structurally related to absinthin, artemorin, amarogentin,arglabin, azathioprine, azepinon, benzoin, brucine, camphor,cascarillin, chlorhexidine, N,N′-diethylthiourea, herbolid A,isohumulone, noscapine, papaverin, parthenolid, picrotoxinin, arborescinor (−)-a-thujon, which may be identified by the methods taught herein,to enhance bitter taste, preferably of an agonist structurally relatedto absinthin, artemorin, amarogentin, arglabin, azathioprine, azepinon,benzoin, brucine, camphor, cascarillin, chlorhexidine,N,N′-diethylthiourea, herbolid A, isohumulone, noscapine, papaverin,parthenolid, picrotoxinin, arborescin or (−)-a-thujon having a structureaccording to formulas (I) to (XIII) as described above, to enhancebitter taste. In this use the bitter taste is preferably mediated by oneor more bitter taste receptor selected from the group consisting ofhTAS2R14, hTAS2R10 and hTAS2R4.

A further aspect of the present invention is the use of an antagonist ofbitter taste receptor activity, which may be identified or produced bythe methods taught herein, in particular an antagonist which isstructurally related to absinthin, artemorin, amarogentin, arglabin,azathioprine, azepinon, benzoin, brucine, camphor, cascarillin,chlorhexidine, N,N′-diethylthiourea, herbolid A, isohumulone, noscapine,papaverin, parthenolid, picrotoxinin, arborescin and (−)-a-thujon,respectively, having a structure according to formulas (I) to (XIII) asdescribed above, to reduce or suppress bitter taste. In this use thebitter taste is preferably mediated by bitter taste receptors selectedfrom the group consisting of hTAS2R14, hTAS2R10 and hTAS2R4 is reducedor suppressed.

The following figures and examples are merely illustrative of thepresent invention and should not be construed to limit the scope of theinvention as indicated by the appended claims in any way.

BRIEF DESCRIPTION OF THE TABLES AND FIGURES

FIG. 1 Chemical structure of artemorin (A), amarogentin (B), arglabin(C), absinthin (D), aborescin (E), noscapine (F), parthenolide (G),isohumulone (H), alpha-thujon (I), cascarillin (J), pictrotoxinin (K),papaverine (L), chlorhexidine (M), camphor (N), brucine (O),azathioprine (P), benzoin (O) and N,N′ diethylthiourea (R).

FIG. 2 Concentration-response curve of the effects of artemorin on theintracellular calcium concentration of HEK293T Gα16gust44 cellsexpressing TAS2R50. The data derived from one experiment carried out intriplicate.

FIG. 3 Detection of hTAS2R4 mRNA in human circumvallate papilla by insitu hybridization.

EXAMPLES Example 1 Functional Expression

Human TAS2R cDNA constructs were used that encoded a plasmamembrane-targeting sequence of the rat somatostatin type 3 receptor atthe N-terminus of the recombinant polypeptide and a herpes simplex virusglycoprotein D (HSV) epitope at its C-terminus (Bufe et al., 2002). Theconstructs were transiently transfected into HEK-293T cells that stablyexpress the chimeric G-protein subunit Gα16gust44 using Lipofectamine2000 (Invitrogen, San Diego, Calif.) in 96-well microtiter plates.Calcium imaging experiments using an automated fluorometric imagingplate reader (FLIPR) (Molecular Devices, Munich, Germany) have beenperformed 24-32 h later essentially as described previously (Bufe etal., 2002). Tastants (Sigma-Aldrich, Taufkirchen, Germany) weredissolved and administered in the following (in mM): 130 NaCl, 5 KCl, 10HEPES, 2 CaCl₂, and 10 mM glucose, pH7.4. Data were collected from 1-2independent experiments performed at least in triplicate and processedwith SigmaPlot (SPSS, Chicago, Ill.). For dose-response curvecalculation, the peak fluorescence responses after compound additionwere corrected for and normalized to background fluorescence(ΔF/F=(F−F₀)/F₀), and baseline noise was subtracted.

Example 2 In Situ Hybridization of Human Vallate Papilla

In situ hybridization was mainly done as before (Behrens et al, Eur JNeurosci 12 (2000) 1372-1384.). Briefly, 20 μm cross-sections ofcircumvallate papillae of human tongues were processed and thaw-mountedonto positively charged glass slides. Prior to hybridisation thesections were postfixated, permeabilised, and acetylated.Prehybridisation was done at 50° C. for 5 h, followed by hybridisationover night at 50° C. After hybridisation the slides were washed severaltimes at low stringency, followed by RNAse A treatment and highstringency washes using 0.4×SSC buffer at 50° C. Hybridised riboprobeswere detected using an anti-Digoxigenin antibody and colourimetry.Photomicrographs were taken with a CCD camera (RT slider, DiagnosticInstruments Inc.) mounted to a Zeiss Axioplan microscope.

Example 3

All 25 human bitter taste receptors were challenged with 100 μMartemorin (FIG. 1) in a FLIPR calcium imaging experiment. Out of these,three receptors, TAS2R14, TAS2R10, and TAS2R4, responded to artemorin ina dose-dependent manner (FIG. 2). Other tested substances elicited nocalcium responses in TAS2R4-expressing cells (not shown). Only if thesecells were challenged with high concentrations (>300 μM) of denatoniumbenzoate and propylthiouracil (PROP), small responses could be detected,which is consistent with previously published results (Chandrashekar etal., Cell 2000). The signal obtained after stimulation with PROP is verysmall (somewhat questionable) and no dose-dependency can be shown as 1mM PROP elicits endogenous signals of mock-transfected cells. Consistentwith the role of TAS2R4 as a bitter taste receptor, we found its mRNA intaste receptor cells of human circumvallate papillae by in situhybridisation (FIG. 3).

Example 4

In an assay similar to the assay described in Example 1 the threereceptors, TAS2R14, TAS2R10, and TAS2R4, also responded to other bittersubstances, when applied at the indicated molar ranges (see Table 1).

TABLE 1 Substanz TAS2R4 TAS2R10 TAS2R14 Absinthin 0.3-0.01 mM 0.1-0.0001mM Amarogentin 1-0.3 mM 1-0.1 mM Arglabin 0.1 mM 0.1 mM Azathioprine0.3-0.1 mM  1-0.1 mM 1-0.01 mM Azepinon 3-0.1 mM Benzoin 0.1-0.01 mM0.1-0.003 mM Brucine 0.3-0.1 mM Camphor 1-0.1 mM 1-0.03 mM 0.1-0.003 mMCascarillin 0.1-0.003 mM Chlorhexidine 0.001-0.000003 mMN,N′-Diethylthiourea 10 mM Herbolid A 1-0.001 mM Isohumulone0.03-0.00003 mM Noscapine 0.01-0.0001 mM Papaverin 0.01-0.0001 mMParthenolid 0.3-001 mM 1-0.001 mM Picrotoxinin 3-0.3 mM Arborescin0.3-0.1 mM 0.3-0.01 mM (−)-a-Thujon 0.3-0.03 mM

1. A method for identifying an antagonist of hTAS2R14 bitter tastereceptor activity, wherein said hTAS2R14 bitter taste receptor activityis mediated by a hTAS2R14 bitter taste receptor comprising: (a) apolypeptide comprising the amino acid sequence according to SEQ ID NO:2; or (b) a polypeptide comprising not more than fifteen (15) amino acidresidues that are conservatively substituted compared to SEQ ID NO: 2and has at least 20% hTAS2R14 bitter taste receptor activity; or (c) apolypeptide having hTAS2R14 bitter taste receptor activity and wheresaid polypeptide is at least 95% identical to a polypeptide having theamino acid sequence according to SEQ ID NO: 2; comprising the steps: (1)contacting a hTAS2R14 bitter taste receptor or a host cell expressingsaid hTAS2R14 bitter taste receptor with a potential antagonist, and (2)determining whether the potential antagonist inhibits the hTAS2R14bitter taste receptor activity; wherein prior, concomitantly and/orafter step (1) said bitter taste receptor or said host cell is contactedwith an agonist of chlorhexidine.
 2. A method for identifying an agonistof hTAS2R14 bitter taste receptor activity, wherein said hTAS2R14 bittertaste receptor activity is mediated by a hTAS2R14 bitter taste receptorcomprising: (a) a polypeptide comprising the amino acid sequenceaccording to SEQ ID NO: 2; or (b) a polypeptide comprising not more thanfifteen (15) amino acid residues that are conservatively substitutedcompared to SEQ ID NO: 2 and has at least 20% hTAS2R14 bitter tastereceptor activity; or (c) a polypeptide having hTAS2R14 bitter tastereceptor activity and where said polypeptide is at least 95% identicalto a polypeptide having the amino acid sequence according to SEQ ID NO:2; comprising the steps: (1) contacting a hTAS2R14 bitter taste receptoror a host cell expressing said hTAS2R14 bitter taste receptor with apotential agonist, and (2) determining whether the potential agonistinduces the hTAS2R14 bitter taste receptor activity; wherein prior,concomitantly and/or after step (1) said bitter taste receptor or saidhost cell is contacted with an agonist of chlorhexidine.
 3. The methodaccording to claim 2, wherein the identified potential agoniststimulates the activity of hTAS2R14 to at least 50% of the activityelicited by chlorhexidine at the same molar concentration.
 4. The methodaccording to claim 1, wherein the identified potential antagonistreduces the activity of hTAS2R14 stimulated by chlorhexidine at least by10% at the same molar concentration.
 5. A method for the production of amodified agonist of hTAS2R14, wherein an agonist identified in a methodaccording to claim 2 is modified by the addition or exchange of at leastone substituent.
 6. The method according to claim 5, wherein a modifiedagonist is selected that stimulates the activity of hTAS2R14 at least asgood as the identified agonist at the same molar concentration.
 7. Amethod for the production of a modified antagonist of hTAS2R14, whereinan antagonist identified in a method according to claim 1 is modified bythe addition or exchange of at least one substituent.
 8. The methodaccording to claim 7, wherein a modified antagonist is selected thatreduces the activity of hTAS2R14 stimulated by chlorhexidine at least asgood as the identified antagonist at the same molar concentration.
 9. Amethod for the production of food, a food precursor material or additiveemployed in the production of foodstuff comprising the step of admixingthe antagonist identified by the method of claim 1, and/or a modifiedantagonist thereof, with foodstuff, a food precursor material oradditive employed in the production of foodstuff.
 10. A method for theproduction of an animal repellent, precursor material or additiveemployed in the production of an animal repellent comprising the step ofadmixing the agonist identified according to the method of claim 2and/or a modified agonist thereof, with an animal repellent or anyprecursor material or additive employed in the production of an animalrepellent.
 11. A method for the production of a nutraceutical orpharmaceutical composition comprising the step of admixing theantagonist identified by the method of claim 1, and/or a modifiedantagonist thereof, with an active agent and optionally withpharmaceutically acceptable carrier and/or adjuvants, in apharmaceutically acceptable form.